Anticoagulation in Anticoagulation in Diagnostic and Diagnostic and

Interventional Procedure Interventional Procedure and Monitoring and and Monitoring and Antiplatelet DrugsAntiplatelet Drugs

Moderator Prof RV PhadkeModerator Prof RV Phadke Presenter Dr Deb K BoruahPresenter Dr Deb K Boruah 2626thth November rsquo09 November rsquo09

The Blood Clotting MechanismThe Blood Clotting MechanismThe three mechanisms of Blood Clotting areThe three mechanisms of Blood Clotting are Vascular SpasmVascular Spasm - The smooth muscle in blood vessel - The smooth muscle in blood vessel

walls contracts immediately the blood vessel is walls contracts immediately the blood vessel is broken This response reduces blood loss for some broken This response reduces blood loss for some time while the other hemostatic mechanisms become time while the other hemostatic mechanisms become activeactive

Platelet Plug FormationPlatelet Plug Formation - When blood platelets - When blood platelets encounter a damaged blood vessel they form a encounter a damaged blood vessel they form a platelet plugplatelet plug to help to close the gap in the broken to help to close the gap in the broken blood vessel (The key stages of this process are blood vessel (The key stages of this process are called called platelet adhesionplatelet adhesion platelet release platelet release reactionreaction and and platelet aggregationplatelet aggregation))

Blood Clotting Blood Clotting (Coagulation)(Coagulation) - - Blood normally remains in its liquid state while Blood normally remains in its liquid state while

it is within the blood vessels but when it leaves it is within the blood vessels but when it leaves them the blood may thicken and form a gel them the blood may thicken and form a gel (coagulation) (coagulation)

Blood clotting (technically Blood clotting (technically blood blood coagulationcoagulation) is the process by which (liquid) ) is the process by which (liquid) blood is transformed into a solid stateblood is transformed into a solid state

bull Interventional procedures

Virchowrsquos Triad

Mechanism of blood Mechanism of blood coagulationcoagulation

HemostasisHemostasis involves a sequence of interactions of coagulation involves a sequence of interactions of coagulation

factor interactions in two pathways called the factor interactions in two pathways called the intrinsic and extrinsic coagulation cascades intrinsic and extrinsic coagulation cascades

The final common pathway involves the The final common pathway involves the transformation of prothrombin to thrombin by factor transformation of prothrombin to thrombin by factor Xa Xa

Thrombin (factor IIa) then serves to catalyze the Thrombin (factor IIa) then serves to catalyze the activation of fibrinogen to fibrin in addition to its role activation of fibrinogen to fibrin in addition to its role in feedback activation of several other clotting factorsin feedback activation of several other clotting factors

UFH LMWH and fondaparinux( saccharides) all UFH LMWH and fondaparinux( saccharides) all exert their anticoagulant effect in a similar fashion by exert their anticoagulant effect in a similar fashion by binding to and activating antithrombinbinding to and activating antithrombin that then that then neutralizes selected coagulation factorsneutralizes selected coagulation factors

Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase

Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply

Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign

surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System

This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue

Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors

2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin

3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot

BLOOD COAGULATION

A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)

Active factors X and V

Prothrombin Thrombin

Fibrinogen Fibrin Fibrin mesh

inhibited by warfarin

inhibited by heparin

Rationale for anticoagulant Rationale for anticoagulant therapytherapy

PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS

Pharmacologic AgentsPharmacologic Agents

AnticoagulantsAnticoagulants

Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)

Anti platelet drugsAnti platelet drugs

Thrombin inhibitorThrombin inhibitor

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)

Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin

AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione

AnisindioneAnisindione

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

The Blood Clotting MechanismThe Blood Clotting MechanismThe three mechanisms of Blood Clotting areThe three mechanisms of Blood Clotting are Vascular SpasmVascular Spasm - The smooth muscle in blood vessel - The smooth muscle in blood vessel

walls contracts immediately the blood vessel is walls contracts immediately the blood vessel is broken This response reduces blood loss for some broken This response reduces blood loss for some time while the other hemostatic mechanisms become time while the other hemostatic mechanisms become activeactive

Platelet Plug FormationPlatelet Plug Formation - When blood platelets - When blood platelets encounter a damaged blood vessel they form a encounter a damaged blood vessel they form a platelet plugplatelet plug to help to close the gap in the broken to help to close the gap in the broken blood vessel (The key stages of this process are blood vessel (The key stages of this process are called called platelet adhesionplatelet adhesion platelet release platelet release reactionreaction and and platelet aggregationplatelet aggregation))

Blood Clotting Blood Clotting (Coagulation)(Coagulation) - - Blood normally remains in its liquid state while Blood normally remains in its liquid state while

it is within the blood vessels but when it leaves it is within the blood vessels but when it leaves them the blood may thicken and form a gel them the blood may thicken and form a gel (coagulation) (coagulation)

Blood clotting (technically Blood clotting (technically blood blood coagulationcoagulation) is the process by which (liquid) ) is the process by which (liquid) blood is transformed into a solid stateblood is transformed into a solid state

bull Interventional procedures

Virchowrsquos Triad

Mechanism of blood Mechanism of blood coagulationcoagulation

HemostasisHemostasis involves a sequence of interactions of coagulation involves a sequence of interactions of coagulation

factor interactions in two pathways called the factor interactions in two pathways called the intrinsic and extrinsic coagulation cascades intrinsic and extrinsic coagulation cascades

The final common pathway involves the The final common pathway involves the transformation of prothrombin to thrombin by factor transformation of prothrombin to thrombin by factor Xa Xa

Thrombin (factor IIa) then serves to catalyze the Thrombin (factor IIa) then serves to catalyze the activation of fibrinogen to fibrin in addition to its role activation of fibrinogen to fibrin in addition to its role in feedback activation of several other clotting factorsin feedback activation of several other clotting factors

UFH LMWH and fondaparinux( saccharides) all UFH LMWH and fondaparinux( saccharides) all exert their anticoagulant effect in a similar fashion by exert their anticoagulant effect in a similar fashion by binding to and activating antithrombinbinding to and activating antithrombin that then that then neutralizes selected coagulation factorsneutralizes selected coagulation factors

Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase

Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply

Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign

surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System

This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue

Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors

2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin

3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot

BLOOD COAGULATION

A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)

Active factors X and V

Prothrombin Thrombin

Fibrinogen Fibrin Fibrin mesh

inhibited by warfarin

inhibited by heparin

Rationale for anticoagulant Rationale for anticoagulant therapytherapy

PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS

Pharmacologic AgentsPharmacologic Agents

AnticoagulantsAnticoagulants

Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)

Anti platelet drugsAnti platelet drugs

Thrombin inhibitorThrombin inhibitor

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)

Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin

AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione

AnisindioneAnisindione

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Blood Clotting Blood Clotting (Coagulation)(Coagulation) - - Blood normally remains in its liquid state while Blood normally remains in its liquid state while

it is within the blood vessels but when it leaves it is within the blood vessels but when it leaves them the blood may thicken and form a gel them the blood may thicken and form a gel (coagulation) (coagulation)

Blood clotting (technically Blood clotting (technically blood blood coagulationcoagulation) is the process by which (liquid) ) is the process by which (liquid) blood is transformed into a solid stateblood is transformed into a solid state

bull Interventional procedures

Virchowrsquos Triad

Mechanism of blood Mechanism of blood coagulationcoagulation

HemostasisHemostasis involves a sequence of interactions of coagulation involves a sequence of interactions of coagulation

factor interactions in two pathways called the factor interactions in two pathways called the intrinsic and extrinsic coagulation cascades intrinsic and extrinsic coagulation cascades

The final common pathway involves the The final common pathway involves the transformation of prothrombin to thrombin by factor transformation of prothrombin to thrombin by factor Xa Xa

Thrombin (factor IIa) then serves to catalyze the Thrombin (factor IIa) then serves to catalyze the activation of fibrinogen to fibrin in addition to its role activation of fibrinogen to fibrin in addition to its role in feedback activation of several other clotting factorsin feedback activation of several other clotting factors

UFH LMWH and fondaparinux( saccharides) all UFH LMWH and fondaparinux( saccharides) all exert their anticoagulant effect in a similar fashion by exert their anticoagulant effect in a similar fashion by binding to and activating antithrombinbinding to and activating antithrombin that then that then neutralizes selected coagulation factorsneutralizes selected coagulation factors

Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase

Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply

Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign

surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System

This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue

Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors

2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin

3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot

BLOOD COAGULATION

A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)

Active factors X and V

Prothrombin Thrombin

Fibrinogen Fibrin Fibrin mesh

inhibited by warfarin

inhibited by heparin

Rationale for anticoagulant Rationale for anticoagulant therapytherapy

PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS

Pharmacologic AgentsPharmacologic Agents

AnticoagulantsAnticoagulants

Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)

Anti platelet drugsAnti platelet drugs

Thrombin inhibitorThrombin inhibitor

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)

Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin

AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione

AnisindioneAnisindione

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

bull Interventional procedures

Virchowrsquos Triad

Mechanism of blood Mechanism of blood coagulationcoagulation

HemostasisHemostasis involves a sequence of interactions of coagulation involves a sequence of interactions of coagulation

factor interactions in two pathways called the factor interactions in two pathways called the intrinsic and extrinsic coagulation cascades intrinsic and extrinsic coagulation cascades

The final common pathway involves the The final common pathway involves the transformation of prothrombin to thrombin by factor transformation of prothrombin to thrombin by factor Xa Xa

Thrombin (factor IIa) then serves to catalyze the Thrombin (factor IIa) then serves to catalyze the activation of fibrinogen to fibrin in addition to its role activation of fibrinogen to fibrin in addition to its role in feedback activation of several other clotting factorsin feedback activation of several other clotting factors

UFH LMWH and fondaparinux( saccharides) all UFH LMWH and fondaparinux( saccharides) all exert their anticoagulant effect in a similar fashion by exert their anticoagulant effect in a similar fashion by binding to and activating antithrombinbinding to and activating antithrombin that then that then neutralizes selected coagulation factorsneutralizes selected coagulation factors

Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase

Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply

Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign

surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System

This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue

Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors

2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin

3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot

BLOOD COAGULATION

A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)

Active factors X and V

Prothrombin Thrombin

Fibrinogen Fibrin Fibrin mesh

inhibited by warfarin

inhibited by heparin

Rationale for anticoagulant Rationale for anticoagulant therapytherapy

PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS

Pharmacologic AgentsPharmacologic Agents

AnticoagulantsAnticoagulants

Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)

Anti platelet drugsAnti platelet drugs

Thrombin inhibitorThrombin inhibitor

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)

Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin

AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione

AnisindioneAnisindione

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Mechanism of blood Mechanism of blood coagulationcoagulation

HemostasisHemostasis involves a sequence of interactions of coagulation involves a sequence of interactions of coagulation

factor interactions in two pathways called the factor interactions in two pathways called the intrinsic and extrinsic coagulation cascades intrinsic and extrinsic coagulation cascades

The final common pathway involves the The final common pathway involves the transformation of prothrombin to thrombin by factor transformation of prothrombin to thrombin by factor Xa Xa

Thrombin (factor IIa) then serves to catalyze the Thrombin (factor IIa) then serves to catalyze the activation of fibrinogen to fibrin in addition to its role activation of fibrinogen to fibrin in addition to its role in feedback activation of several other clotting factorsin feedback activation of several other clotting factors

UFH LMWH and fondaparinux( saccharides) all UFH LMWH and fondaparinux( saccharides) all exert their anticoagulant effect in a similar fashion by exert their anticoagulant effect in a similar fashion by binding to and activating antithrombinbinding to and activating antithrombin that then that then neutralizes selected coagulation factorsneutralizes selected coagulation factors

Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase

Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply

Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign

surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System

This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue

Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors

2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin

3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot

BLOOD COAGULATION

A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)

Active factors X and V

Prothrombin Thrombin

Fibrinogen Fibrin Fibrin mesh

inhibited by warfarin

inhibited by heparin

Rationale for anticoagulant Rationale for anticoagulant therapytherapy

PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS

Pharmacologic AgentsPharmacologic Agents

AnticoagulantsAnticoagulants

Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)

Anti platelet drugsAnti platelet drugs

Thrombin inhibitorThrombin inhibitor

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)

Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin

AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione

AnisindioneAnisindione

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

HemostasisHemostasis involves a sequence of interactions of coagulation involves a sequence of interactions of coagulation

factor interactions in two pathways called the factor interactions in two pathways called the intrinsic and extrinsic coagulation cascades intrinsic and extrinsic coagulation cascades

The final common pathway involves the The final common pathway involves the transformation of prothrombin to thrombin by factor transformation of prothrombin to thrombin by factor Xa Xa

Thrombin (factor IIa) then serves to catalyze the Thrombin (factor IIa) then serves to catalyze the activation of fibrinogen to fibrin in addition to its role activation of fibrinogen to fibrin in addition to its role in feedback activation of several other clotting factorsin feedback activation of several other clotting factors

UFH LMWH and fondaparinux( saccharides) all UFH LMWH and fondaparinux( saccharides) all exert their anticoagulant effect in a similar fashion by exert their anticoagulant effect in a similar fashion by binding to and activating antithrombinbinding to and activating antithrombin that then that then neutralizes selected coagulation factorsneutralizes selected coagulation factors

Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase

Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply

Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign

surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System

This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue

Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors

2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin

3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot

BLOOD COAGULATION

A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)

Active factors X and V

Prothrombin Thrombin

Fibrinogen Fibrin Fibrin mesh

inhibited by warfarin

inhibited by heparin

Rationale for anticoagulant Rationale for anticoagulant therapytherapy

PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS

Pharmacologic AgentsPharmacologic Agents

AnticoagulantsAnticoagulants

Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)

Anti platelet drugsAnti platelet drugs

Thrombin inhibitorThrombin inhibitor

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)

Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin

AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione

AnisindioneAnisindione

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase

Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply

Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign

surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System

This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue

Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors

2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin

3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot

BLOOD COAGULATION

A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)

Active factors X and V

Prothrombin Thrombin

Fibrinogen Fibrin Fibrin mesh

inhibited by warfarin

inhibited by heparin

Rationale for anticoagulant Rationale for anticoagulant therapytherapy

PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS

Pharmacologic AgentsPharmacologic Agents

AnticoagulantsAnticoagulants

Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)

Anti platelet drugsAnti platelet drugs

Thrombin inhibitorThrombin inhibitor

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)

Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin

AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione

AnisindioneAnisindione

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

BLOOD COAGULATION

A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)

Active factors X and V

Prothrombin Thrombin

Fibrinogen Fibrin Fibrin mesh

inhibited by warfarin

inhibited by heparin

Rationale for anticoagulant Rationale for anticoagulant therapytherapy

PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS

Pharmacologic AgentsPharmacologic Agents

AnticoagulantsAnticoagulants

Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)

Anti platelet drugsAnti platelet drugs

Thrombin inhibitorThrombin inhibitor

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)

Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin

AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione

AnisindioneAnisindione

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Rationale for anticoagulant Rationale for anticoagulant therapytherapy

PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS

Pharmacologic AgentsPharmacologic Agents

AnticoagulantsAnticoagulants

Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)

Anti platelet drugsAnti platelet drugs

Thrombin inhibitorThrombin inhibitor

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)

Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin

AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione

AnisindioneAnisindione

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS

Pharmacologic AgentsPharmacologic Agents

AnticoagulantsAnticoagulants

Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)

Anti platelet drugsAnti platelet drugs

Thrombin inhibitorThrombin inhibitor

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)

Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin

AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione

AnisindioneAnisindione

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Pharmacologic AgentsPharmacologic Agents

AnticoagulantsAnticoagulants

Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)

Anti platelet drugsAnti platelet drugs

Thrombin inhibitorThrombin inhibitor

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)

Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin

AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione

AnisindioneAnisindione

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

ANTICOAGULANTSANTICOAGULANTS

Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)

Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin

AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione

AnisindioneAnisindione

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

Clopidegrel)Clopidegrel)

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide Eptifibatide (Integrilin)(Integrilin)

TirofibaTirofibann

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses

Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution

Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery

Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY

Narrow therapeutic rangeNarrow therapeutic range

Can increase risk of bleedingCan increase risk of bleeding

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Coagulation TestingCoagulation Testing

Monitoring therapyMonitoring therapy

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

CLOT

Heparin Coumadin

Monitor with

ACT aPTT

Monitor with PTINR

Thrombolytics

Monitor with TT Fibrinogen

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

HeparinHeparin

Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight

Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)

About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex

Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them

Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins

Structure and sequence

O

OH

OH

O

COO

O

O

CH2OH

NHSO3

OH

_

_

O

O

CH2OSO3

NHSO3

OH

_

_

O

OH

OH

O

COOO

O

CH2OSO3

NHSO3

OH

_

_

O

OSO3

OHO

COOO

O

CH2OSO3

NHCOCH3

OH

_

_ _

_

_

O

OH

OH

O

COO

1

23

4

5

6

-D-glucosamine -L-iduronic acid -D-glucuronic acid

O

O

CH2OH

NH2

OH 12

3

4

5

6

O

OH

OHO

COO_

1

23

4

5

6

polymeric structure of heparin

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin

11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin

22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)

33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme

44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be

administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract

Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Monitoring of heparin Monitoring of heparin

Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous

Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)

Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)

Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies

Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

ACT or aPTTACT or aPTT

Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site

ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds

aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in

plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)

Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour

Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)

(AJNR 199415 51-54)

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))

Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two

days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence

The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation

Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients

receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

(AJNR 28155-158 2007)

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia

When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH

Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered

The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION

Inactive factors II VII IX and X

Proteins S and C

Active factors II VII IX and X

Proteins S and C

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

Antagonist is Vit KAntagonist is Vit K

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications

Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS

started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days

Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

20-3020-30

Treatment of venous Treatment of venous thromboembolismthromboembolism

20-3020-30

Atrial fibrillationAtrial fibrillation 20-3020-30

Mitral valve stenosisMitral valve stenosis 20-3020-30

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

20-3020-30

25-3525-35

Myocardial infarctionMyocardial infarction 20-3020-30

25-35 25-35 (high risk patients)(high risk patients)

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Contraindication for WarfarinContraindication for Warfarin

Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)

Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma

As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously

PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR

Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT

May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient

PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample

ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index

Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Heparin versus WarfarinHeparin versus Warfarin

Drug ActionMechan-ism

Moni-toring

Effective

HeparinDirect

Inhibition ofThrombin

ATIIIcofactor

APTTACT

Immediate

WarfarinDecreasesProductionof factors

Vitamin K PTDelay

3-5 days

INR

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies

Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or

thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented

fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke

IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial

vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus

This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion

Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic

With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced

Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours

IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level

of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability

Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

ThrombolyticsThrombolytics

Plasminogen activators

Fibrinolytics

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts

First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C

szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18

UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity

The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)

is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity

Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg

Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion

Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Third-Generation AgentsThird-Generation Agents

ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase

with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity

TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer

half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater

resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke

suggest that the drug is safe and promisingsuggest that the drug is safe and promising

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Newer plasminogen activatorNewer plasminogen activator

DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor

found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound

plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator

Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH

The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents

AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen

and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also

leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain

In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

2 Direct Fibrinolytics2 Direct Fibrinolytics

Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects

of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with

microplasminmicroplasmin

Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase

isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent

of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of

delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Anti-fibrinolyticsAnti-fibrinolytics

to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from

binding to fibrinbinding to fibrin

alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin

Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists

such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical

thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is

possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours

Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis

Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical

devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)

fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories

Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents

Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery

Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm

Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial

punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy

Thrombin time Measures the availability of functional

fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below

75-100 mgdl

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life

Streptokinase IA 60-80min

Urokinase IAIV 9-12min

rTPA IAIV 6min

Abciximab(Reopro) IAIV 12hour

Aspirin POIV 15-20min

Heparin IVSC 60min

Coumadin PO 15-25 days

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits

COX-1 and COX-2COX-1 and COX-2CADCAD

Stroke-TIAsStroke-TIAs

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP

TIAsTIAs

ThenopyridinesThenopyridines

(Ticlopidine(Ticlopidine

ClopidrgrelClopidrgrel))

Inhibits ADP Inhibits ADP

PlatAg PlatAg

TIAsStrokeTIAsStroke

CAD PVDCAD PVD

Abciximab (ReoPro)Abciximab (ReoPro)

Eptifibatide (Integrilin)Eptifibatide (Integrilin)

TirofibanTirofiban

GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors

Stroke- TIAs Stroke- TIAs

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

MonitoringMonitoring

Bleeding timeBleeding time

Optical aggregometryOptical aggregometry

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Bleeding timeBleeding time

Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of

a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)

AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside

DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique

Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Optical aggregometryOptical aggregometry

Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different

agentsagents However require unique expertise and are not However require unique expertise and are not

universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70

aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means

resistance) resistance)

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay

Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different

agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents

For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)

Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Practical Applications Practical Applications related to specific related to specific

Neurovascular Neurovascular interventionsinterventions

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected

differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow

Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin

Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs

If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly

Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored

Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic

StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the

with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus

Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome

Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment

Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter

angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for

evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography

what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation

Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA

Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli

aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot

(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized

clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as

decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)

Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd

territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT

Intra-arterial Thrombolysis

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets

PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)

This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics

So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs

rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or

Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by

0125 ugkgmin)0125 ugkgmin)

++

Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion

with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding

Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000

IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000

IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Intravenous ThrombolysisIntravenous Thrombolysis

The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue

IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS

Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Intravenous rTPA Intravenous rTPA administration administration protocolprotocol

Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)

Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for

monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes

during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA

Protocol limit = 3 hrs

Benefit ~ 45 hrs

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are

- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization

- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures

- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation

- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement

- Slow flow dt vasospasm - Slow flow dt vasospasm

- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT

Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Current regimen of endovascular Current regimen of endovascular managementmanagement

The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)

Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by

ACT) ACT) Intravenous aspirin Intravenous aspirin

Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate

thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or

post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined

but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-

procedureprocedureOrOr

Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on

morning of proceduremorning of procedure

If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than

Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)

Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Carotid StentingCarotid Stenting

Pre-procedurePre-procedure

Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3

days before the proceduredays before the procedure

Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure

Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec

Post-procedure Post-procedure

Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and

Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission

with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram

b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space

Treatment Options for Venous Thrombosis

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change

(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)

Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect

Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect

Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect

Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Local ThrombolysisLocal Thrombolysis

Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram

Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used

After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Low-molecular-weight Low-molecular-weight heparinheparin

PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately

one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious

depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn

Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains

required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin

relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific

binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable

pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also

allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin

They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Few Experiences of Few Experiences of ThrombolysisThrombolysis

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia

MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal

aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery

Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with

Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post

procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include

presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent

surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral

Ischemia) retrievalIschemia) retrieval system system

Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries

In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset

Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients

with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67

Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot

extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction

First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot

successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy

06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)

achieved a higher recanalization rateachieved a higher recanalization rate

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA

Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic

strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit

Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to

neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere

on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110

mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006

IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window

MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)

Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

rt-PA Trials NINDSrt-PA Trials NINDS

Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30

more like to have minimal or no disabilitymore like to have minimal or no disability

First proven approved treatment for First proven approved treatment for strokestroke

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)

Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to

bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests

Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)

Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days

Baseline 60 minutes 120 minutes

9mg IAProurokinase

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS

Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo

controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat

salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch

MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger

than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on

raw imagesraw imagesMRI ExclusionMRI Exclusion

DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices

mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus

The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse

Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices

suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to

create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction

The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress

Most devices are used in cerebral vessels that 2-5 mm

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be

treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral

Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)

A laser power source generated energy for the A laser power source generated energy for the systemsystem

The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site

Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip

the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light

Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic

Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with

infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter

Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution

The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot

After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter

the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes

One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual

approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed

Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)

a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke

The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel

Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant

Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes

These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the

catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical

San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it

The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction

Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the

simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with

a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis

Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus

A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid

bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive

Summary Acute Stroke Summary Acute Stroke ImagingImaging

PhysiologyPhysiology importance collaterals importance collaterals

ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment

tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch

ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and

comprehensivecomprehensive