Anesthesia for patients on anti- coagulant therapy

Moderator- Prof Jyotsna AgarwalPresented by- Dr Navin Jain

Dr Shubham Kr Dr Pramod Kr Singh

Coagulation Cascade

When are anticoagulants indicated Prophylactic

AF (Atrial fibrillation)

Artificial valve replacement

Deep vein thrombosis

Pulmonary hypertension.

Cardiomyopathy.

Unstable angina

Congenital heart disease.

Therapeutic Pulmonary embolism.

Ischemic stroke.

Coronary artery bypass graft

surgery.

Angioplasty and stenting

Coronary artery disease.

Peripherial arterial disease.

Retinal vessel thrombosis.

Common anticoagulants encountered in the surgical setting.

1) Anti-platelet medications-a) Aspirin, NSAIDs, COX-2 inhibitorsb)Thienopyridin derivatives- Clopidogrel, Ticlopidinec)GPIIb/IIIa inhibitors- Abciximab, Eptifibatide,

Tirofiban2) Oral anticoagulants- Warfarin sodium, Dicumarol3) Unfractionated Heparin4) Low molecular weight heparin- Enoxaparin, Dalteparin, Tinzaparin5) Specific Xa inhibitors- Fondaparinux6) Direct Thrombin Inhibitors- Lepirudin, Bivalirudin, Ximelgatran, Argatroban7)Fibrinolytic/Thrombolytic drugs- Streptokinase, Urokinase, Reteplase,

Alteplase, Tenecteplase8)Herbal Therapy- Garlic, Ginkgo, Ginseng

CYCLOOXYGENASE INHIBITORS

COX inhibitors include:

(1)Non selective inhibitors (Aspirin and NSAIDs) and

(2) Selective agents inhibiting only COX-2.

Aspirin irreversibly inhibits COX-1-mediated platelet granule

release over the platelet’s lifetime (7-10 days).

NSAIDs (naproxen, piroxicam, and ibuprofen) reversibly inhibit

platelet COX and prevent thromboxane A2 synthesis.

ASRA recommendations for Aspirin and NSAIDs

•Either medication alone does not increase risk.•Need to scrutinize dosages, duration of therapy and concomitant medications that may affect coagulation.•No wholly accepted laboratory tests. A normal bleeding time does not indicate normal homeostasis. An abnormal bleeding time does not necessarily indicate abnormal homeostasis.

THIENOPYRIDINE DERIVATIVESThe thienopyridine derivatives ticlopidine and clopidogrel interfere with

platelet function by interfering with fibrinogen binding to platelets and thus

inhibiting ADP induced primary and secondary platelet aggregation.

ASRA recommendations: Clopidogrel- discontinue for 7 days

Ticlopidine- discontinue for 14 days

GPIIb/IIIa ANTAGONISTSAvailable GPIIb/IIIa platelet receptor antagonists include abciximab,

eptifibatide, and tirofiban.

These drugs are potent inhibitors of platelet aggregation because binding of

fibrinogen and vWF to platelet GPIIb/IIIa receptors is blocked.

ASRA recommendations: Abciximab- 48hrs

Eptifibatide- 8hrs

Tirofiban- 8hrs

American Association of Regional Anesthesia Guidelines for Neuraxial Anesthesia in Anticoagulated Patients

Medication Recommendation

NSAIDS No contraindication

Aspirin No contraindication

Ticlopidine Discontinue 14 days preoperative

Clopridogrel Discontinue 7 days preoperative

GP IIb/IIIa inhibitors

Abciximab Discontinue 48 hrs preoperative

Eptifibatide Discontinue 8 hours preoperative

Tirofiban Discontinue 8 hrs preoperative

ASA Practice Advisory 2010

Warfarin (Coumadin)

• MECHANISM OF ACTION: Inhibits vitamin K formation by inhibiting the

enzyme Vitamin K epoxide reductase(VKOR). Depletion of the vitamin K dependent proteins (prothrombin and factors VII, IX and X) occurs.

• DURATION OF ACTION: Onset is 8-12 hours with a peak at 36-72 hours.

Warfarin and General Anesthesia

Preoperative• Discontinue warfarin at least 5 d before elective procedure• Assess INR 1 to 2 d before surgery, if >1.5, consider 1-2 mg of

oral vitamin K• Reversal for urgent surgery/procedure- consider 2.5-5 mg of

oral or intravenous vitamin K; for immediate reversal, consider

fresh-frozen plasma• Patients at high risk for thromboembolism

Bridge with therapeutic subcutaneous LMWH (preferred) or

intravenous UFH Last dose of preoperative LMWH administered 24 hrs before

surgery, administer half of the daily dose Intravenous heparin discontinued 4 hrs before surgery

• No bridging necessary for patients at low risk for

thromboembolism

Postoperative• Patients at low risk for thromboembolism

Resume warfarin on postoperative day• Patients at high risk for thromboembolism (who

received preoperative bridging therapy) Minor surgical procedure--resume therapeutic LMWH

24 hrs postoperatively Major surgical procedure--resume therapeutic LMWH

48 to72 hrs postoperatively or administer low-dose LMWH

• Assess bleeding risk and adequacy of haemostasis when considering timing of the resumption of LMWH or UFH therapy

ASA Practice Advisory 2010

Peri- operative management –Warfarin

ASA Practice Advisory 2010

Warfarin and Neuraxial Anesthesia

• The current ASRA guidelines recommends an INR value of ≤1.4 as acceptable for the performance of neuraxial blocks

• The concurrent use of other medications, such as aspirin, NSAIDs, and heparins that affect the clotting mechanism, increases the risk of bleeding complications without affecting the INR.

• A controversy exists regarding whether or not the epidural catheter can be removed on postoperative day 1, or 12-14 hours after warfarin is started, when the INR is >1.4. In the absence of other risk factors for increased bleeding, the catheter can probably be removed.

• The factor VII activity should be determined if risk factors such as low platelets, advanced age, kidney failure, or intake of other anticoagulants are present

Warfarin

Neuraxial intervention

Stop warfarin 4 to 5 days preoperatively, normal INR(<1.4) before intervention

After intervention Remove catheter when INR <= 1.4

Standard Heparin

• MECHANISM OF ACTION:Binds with antithrombin III, producing a

conformational change and scaffolding in it that exposes the binding sites, thus inactivating factor Xa and IIa respectively.

• DURATION OF ACTION: The elimination half life for IV heparin is 56

minutes.

ASRA recommendations for Standard Heparin

• Mini-dose subcutaneous heparin(5000 IU twice daily) does not contraindicate a neuraxial block. The administration of subcutaneous heparin should be withheld until after the block.

• Patients should be screened for concurrent anticoagulant medications that may impact clotting.

• Patients on heparin for more than 5 days should have a platelet count assessed prior to neuraxial blockade due to the risk of heparin induced thrombocytopenia.

contd...

• Intravenous Heparin administration should be delayed for 1 hour after neuraxial blockade.

• Indwelling catheters should be removed 2-4 hours after the last dose and evaluation of APTT. Intravenous Heparin should not be re-initiated until 1 hour has passed.

• If a “bloody tap” has occurred it should be communicated to the surgeon. No data suggests the mandatory cancellation of the surgical case.

Unfractionated Heparin

Sub –Cutaneous

(usually given for prophylaxsis)

Neuraxial intervention

No contraindication, measure platelet count, if more than 4 days of heparin treatment.

After intervention

if more than 4 days of heparin treatment measure platelet count before removing catheter.

Intra venous

Vascular surgery and

Neuraxial intervention

Avoid in presence of other coagulopathies. Delay heparin for 1 hour after catheter placement, no

restriction before procedure with dosing every 12 hours, delay if difficult catheter placement is

anticipated

After intervention

Catheter removal 2 to 4 hours after heparin and normal PTT & ACT

ASA Practice Advisory 2010

LOW MOLECULAR WEIGHT HEPARIN

LMWH is produced by cleaving heparin into shorter fragments.

LMWH only causes conformational change in ATIII and inhibits only factor

Xa. LMWH has a delayed onset of 20 to 60 minutes and a longer half-time

than heparin and can be administered subcutaneously either once or

twice daily and require less monitoring (anti-Xa levels) or no monitoring.

Have predictable pharmacokinetics and fewer effect on platelet function.

Disadvantages of LMWH include less reliable reversal with protamine and

increased risk of bleeding during long-term use compared to

unfractionated heparin.

ASRA recommendations for LMWH

1. Preoperative LMWH :

• If LMWH has been administered preoperatively, then LMWH should be held for 12 hrs

prior to a neuraxial technique.

2. Postoperative LMWH:

• Avoid other drugs that affect hemostasis.

• Presence of blood during needle or catheter placement does not necessitate

postponement of surgery. In those cases the first dose of LMWH should be delayed for 24

hrs postoperatively

• Twice daily dosing. It is recommended that the first dose of LMWH be administered no

earlier than 24 hours postoperatively. Indwelling catheters should be removed prior to

initiation of LMWH thromboprophylaxis.

• Single daily dosing. It is recommended that the first postoperative LMWH dose be

administered no sooner than 6-8 hours postoperatively. The second postoperative dose

should occur no sooner than 24 hours after the first dose.

LMWH

Before Neuraxial intervention

Delay 10 – 12 hours after dose. Delay 24 hours after traumatic (bloody) tap or with twice daily

dosing.

After intervention

Once daily dosing :Remove catheter 10-12 hours after last dose and

start next dose 2 hours later

Twice daily dosing :Remove catheter 2 hours before 1st dose.

Fondaparinux

• Antithrombotic medication for DVT prophylaxis• Binds with antithrombin III which neutralizes factor Xa.• Peak effect in 3 hours with half life of 17-21 hours• Irreversible effect• ASRA recommendation: if neuraxial procedure has to be

performed then it is recommended to do a single needle, atraumatic placement, and avoid indwelling catheter

• Expert study recommends epidural placement/removal to be done after 36hrs of fondaparinux dose and subsequent dose to be given after 24hrs.

New anticoagulants

Direct Thrombin Inhibitors• Bivalirudin- thrombin inhibitor used in interventional

cardiology.• Lepirudin used to treat heparin-induced thrombocytopenia.• Caution advised. No recommendations related to limited

clinical experience.

Direct Factor Xa Inhibitors-• Rivaroxaban is an oral, reversible, direct factor Xa inhibitor

that is rapidly absorbed. Howerer apixaban also has the same MOA but irreversible

Thrombolytic and Fibrinolytic Medications• Thrombolytics are classified as native tissue

plasminogen activators, streptokinase and urokinase, or as exogenous tissue plasminogen activator formulations, alteplase ,reteplase, tenecteplase

• Original recommendation was to withhold neuraxial blockade for 10 days.

• No data concerning the length of time that neuraxial blockade should be withheld.

• If a patient has received a neuraxial block and unexpectantly receives thrombolytic/fibrinolytic therapy then monitor patient for neurological complications.

• No recommendations related to the removal of epidural catheters in the patient who unrepentantly receives thrombolytic/fibrinolytic therapy.

Thrombo lytics

Neuraxial intervention Absolute containdication the first 10 days.

After interventionRemove catheter with fibrinogen level normalize and

should also check neurologically (i.e. sensory and motor)

ASA Practice Advisory 2010

Herbal MedicationsHerbal Medicine Mechanism of Action Time to normal

haemostasis

1.) Garlic •Inhibits platelet aggregation•Increased Fibrinolysis

7 Days

2.) Ginkgo • Inhibits platet- activating factor

36 hours

3.) Ginseng • Increased PT and aPTT 24 hours

ASRA recommendations: Neuraxial block not contraindicated for single herbal medication use

Anticoagulation and peripheral nerve blockade

• Case reports of major bleeding occurring with psoas compartment and lumbar sympathetic blocks.

• Patients with neurological deficits had complete recovery in 6-12 months. The key to this reversal was the fact that bleeding occurred in expandable and compressible tissue as opposed to the non-expandable compartments associated with neuraxial blockade.

Type of Procedure Platelets in /uL

Minimally invasive procedures (central line placement, angiography, thoracocentesis, and paracentesis,endoscopy,biopsy)

>30,000

Epidural catheter insertion or removal Ranges from50,000 to 80,000

Operative procedures ordinarily associated with insignificant blood loss

>50,000

Surgery within a closed space such as in neurosurgery and ophthalmic surgery

>100000

Lumbar puncture or spinal or vaginal delivery >50,000

Microvascular bleeding attributed to platelet dysfunction, for example, uremia, a post cardiopulmonary bypass, or in association with massive transfusion

Clinical judgement

Proposed guidelines for platelet transfusion,BCMJ 2005

Epidural Space vs Intrathecal Space

• Epidural space is richly supplied with a venous plexus • Area around the spinal cord is fixed. Bleeding results

in compression, ischemia, nerve trauma, and paralysis.

• Bleeding into the intrathecal space is diluted by the Cerebral Spinal Fluid (which is usually less devastating)

Risk Factors for the Development of Epidural Hematoma

• Anatomic abnormalities of the spinal cord or vertebral column

• Vascular abnormalities • Pathologic/medication induced alterations in

homeostasis• Alcohol abuse• Chronic renal insufficiency• Difficult and traumatic needle placement• Epidural catheter removal

Signs and Symptoms of an Epidural Hematoma

• Low back pain (sharp and irradiating)• Sensory and motor loss (numbness and

tingling/motor weakness long after block should have abated)

• Bowel and/or bladder dysfunction• Paraplegia

Treatment and Outcome

• Must be treated within 8-12 hours of onset of symptoms

• Emergency decompressive laminectomy with hematoma evacuation

• Outcome is generally poor

Anticoagulation in patients with prosthetic valve

INDICATIONS:-• Lifelong for all patients with mechanical valves• Lifelong for patients with bioprosthesis who have other indications for

anticoagulation, e.g. atrial fibrillation• For the first 3 months after insertion in all patients with bioprosthesis with

a target INR of 2.5

RISK FACTORS• The risk of embolization is greater with prosthetic mitral valve than

prosthetic aortic valve• Atrial fibrillation, LV dysfunction, clotting disorder, prior embolic events

TARGET INR:- 2.5- 3.5

RECOMMENDATIONS:-• Aspirin is recommended for all patients with bioprosthesis: aspirin alone

(75-100 mg per day) in patients with bioprosthesis and no risk factors or aspirin combined with warfarin in patients with mechanical heart valves and high-risk patients with bioprosthesis.

• For minor surgeries where bleeding is easily controlled, anticoagulation should be given with a target of 2.0

• For major surgical procedures in which anticoagulation interruption is considered essential(INR < 1.5) , patients should be admitted to the hospital in advance and transferred to intravenous unfractionated heparin. Heparin is stopped 6 hrs before surgery and resumed 6-12hrs after. This technique is termed as ‘bridging anticoagulation’

Anesthetic implications of anticoagulants in patients with coronary stents

• Elective surgery postponed for the following durations ifaspirin and thienopyridine (eg, clopidogrel) needs to be discontinuedo Bare metal stents: 4-6 wko Drug-eluting stents: 12 mo

• If surgery cannot be postponed, continue aspirin throughoutperioperative period

• Patients at high risk for cardiac events (exclusive of coronary stents)o Continue aspirin throughout the perioperative periodo Discontinue clopidogrel at least 5 d (and preferably 10 d) before surgeryo Resume clopidogrel 24 hrs postoperatively

• Patients at low risk of cardiac eventso Discontinue antiplatelet therapy 7Y10 d before surgeryo Resume antiplatelet therapy 24 hrs postoperatively

PROSTHETIC VALVE IN PREGNANCY

Pregnancy in a woman with mechanical valve is associated with an estimated maternal mortality of 1 to 4 % with death usually resulting from complications of prosthetic valve thrombosis.

Before Conception:• Clinical evaluation of cardiac functional status and previous cardiac events• Echocardiographic assessment of ventricular and valvular function and

pulmonary pressure• Discussion of risks associated with pregnancy and use of anticoagulation.• Family planningConception• Change to unfractionated heparin(APTT ratio should be maintained above

2.0) from time of confirmed pregnancy upto week 12.

Completion of First Trimester:• Warfarin therapy, 12- 36 weeks

Week 36:• Discontinue warfarin• Change to unfractionated heparin titrated to a therapeutic APTT time or

factor Xa level.Delivery:• Heparin should be discontinued at the start of labour• Oral anticoagulation should be resumed after 24hrs if no concerns

regarding bleeding• Restart heparin therapy 4 to 6 hours after delivery if no contraindications• If labour occurs preterm while the patient is till on anticoagulant use, a

caesarean section should be performed after reducing the INR to 2.0 • A vaginal delivery should be avoided under oral anticoagulation because

of danger of fetal intracranial bleeding.

MCQS

1. Following hypercoagulable states are classified under high risk for peri-operative thrombosis except:1)Protein C deficiency2)Protein S deficiency3)Heparin-induced thrombocytopenia4)Factor V Leiden genetic polymorphism

Answer: 4Protein c, protein s deficiency is a procoagulant stateIn heparin induced thrombocytopenia, there is relative decrease in platelets due to consumptive coagulopathy but there is increased venous thrombosisMiller’s 8th ed

2) Following are true about HIT (heparin induced thrombocytopenia) except:1)Absolute or relative (=/> 50 percent) reduction in platelet count during or after heparin administration.2)A direct thrombin inhibitor (i.e., bivalirudin, lepirudin, argatroban) is substituted for heparin3)HIT manifests clinically as thrombocytopenia occurring 5 to 14 days after initiating heparin4)PF4/heparin immune complexes clear from the circulation within 30 days.

Answer: 4the first 3 options are correctplatelet immune complexes clear much fasterMiller’s 8th ed

3) Which of the following is true about ACT (activated clotting time):1)The ACT in normal individuals is 75-80 seconds2)ACT measures clot formation by way of intrinsic and common pathways3)Celite is recommended for use in patients receiving the antifibrinolytic drug aprotinin4)After surgical incision, baseline ACT usually increases

Answer:- 2Normal ACT- 107+-13secKaolin is recommended in pt receiving aprotinin

as celite shows false ACT in such ptAfter surgical incision, ACT decreasesMiller’s 8th ed

4)Correct statements about the action of warfarin include:A. warfarin is structurally similar to vitamin K and competitivelyinhibits liver synthesis of clotting factorsB. warfarin inhibits vitamin K epoxide reductaseC. the onset of warfarin action may be prolonged due to the long half-life of factor VIID. factors II, VII, IX, and X are not activated (carboxylated) when warfarin is administered in therapeutic doses1. A,B,C2. A,C3. B,D4. D only5. All of the above

• Answer:- 3Options B and D are correctWarfarin inhibits VKOR vitamin K epoxide

reductase which is primarily responsible for the regeneration of Vit k after its does gamma carboxylation of factor 2,7,9,10

Factor 7 has the shortest half life-6hrs among all the factors

Competitive pharmacology

5)The mechanism of action of mini-dose heparin is correctly described by:A. factor X is more sensitive to heparin than are other serineprotease factorsB. mini-dose heparin is useful prophylactically rather than during active clot formationC. by inhibiting factor X activation, a relative block of theclotting cascade develops, with less thrombin formedD. the major action is to directly inhibit factor II, which is verysensitive to heparin1. A,B,C2. A,C3. B,D4. D only5. All of the above

Answer:- 1Options a,b,c are correctMini dose heparin includes heparin 5000IU scIt is used as thromboprophylaxisFactor X is more sensitive to inhibition than

Factor 2

6) Heparin does not cause:-a) Osteoporosisb) Factor V inhibitionc) Thrombocytopeniad) Prolongs aPTT

Answer:- BHeparin causes a decrease in calcium(Factor 4)

and hence all females of child bearing age should receive calcium when the receive heparin

Heparin induced thrombocytopenia is a well known complication

Heparin prolongs aPTTCompetitve pharmacology

7) You started a patient on oral warfarin. Which of the following factors show the most rapid decline in the blood levels after the initiation of warfarin therapy?

a) Factor VIIb) Protein Cc) Factor Xd) Prothrombin

Answer:- 1Factor 7 has the least half life i.e. 6 hrsWhereas factor 2(prothrombin) has the highest

half life i.e. 60hrsCompetitve pharmacology

8) Warfarin induced skin necrosis and hypercoagulation is seen in:

a) Protein C deficiencyb) Protein S deficiencyc) Haemophiliad) Antithrombin III deficiencye) Factor VII deficiency

Answer:- 1Heparin in addition to inhibition of factor

2,7,9,10 also inhibits protein C,SProtein C,S are thrombolytics in our bodyProtein C half life is 8hrsHence its inhibition causes a hypercoagulant

state known as Dermal Vascular NecrosisCompetitive pharmacology

9) Excessive anticoagulant effect in bleeding due to warfarin can be reversed by(multiple answer) :

A) stopping the drugB) large doses of vitamin KC) factor IX concentratesD) cholestyramineE) diuretics

Answer:- 1,2,3Stopping warfarin, vit K and Factor 9

concentrates can reverse the effects of warfarin

For acute reversal FFP/CryopptCompetitve pharmacolgy

10) Which of the following is NOT an advantage of low molecular weight heparin over unfractionated heparin?

a) Higher efficacy in arterial thrombosisb) Less frequent dosingc) Higher and more consistent subcutaneous

bioavailabilityd) Laboratory monitoring of response not

required

Answer:- 1Arterial thrombus is mainly formed by platelets

and hence anti-platelet drugs are indicated in arterial thrombosis

Venous thrombus is mainly formed of fibrin and hence anticoagulants are indicated in venous thrombosis

Rest all are advantages of LMWH over UFHCompetitve pharmacology