Disseminated Intravascular Coagulation Keith Lewis, MD

Disseminated Intravascular Coagulation

Keith Lewis, MD.Keith Lewis, MD.

DIC

An acquired syndrome An acquired syndrome characterized by characterized by systemicsystemic intravascularintravascular coagulationcoagulation

Coagulation is Coagulation is alwaysalways the the initial event.initial event.

Most morbidity and Most morbidity and mortality depends on extent mortality depends on extent of intravascular thrombosisof intravascular thrombosis

Multiple causesMultiple causes

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ThrombosisThrombosis

FibrinFibrin

Red Blood CellRed Blood Cell

PlateletPlatelet

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Hemostasis Review

Coagulation cascadeCoagulation cascade Vascular EndotheliumVascular Endothelium Anticlotting MechanismsAnticlotting Mechanisms Fibrinolytic SystemFibrinolytic System PlateletsPlatelets Blood Flow DynamicsBlood Flow Dynamics

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HemostasisHemostasisSubendothelialSubendothelial matrix matrix

PlateletsPlatelets

HemostaticHemostatic plug plug

FibrinFibrin

Endothelial cellEndothelial cell

RBCRBCWBCWBC

WBCWBC

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Vascular Endothelium

Vascular endothelium Vascular endothelium expressesexpresses: : ThrombomodulinThrombomodulin Tissue Plasminogen Tissue Plasminogen

ActivatorActivator Tissue Tissue

thromboplastin/Tissue thromboplastin/Tissue factorfactor

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HemostasisHemostasisSubendothelialSubendothelial matrix matrix

PlateletsPlatelets

HemostaticHemostatic plug plug

FibrinFibrin

Endothelial cellEndothelial cell

RBCRBCWBCWBC

WBCWBC

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Coagulation Intrinsic PathwayIntrinsic Pathway Extrinsic PathwayExtrinsic Pathway Common PathwayCommon Pathway Contact PathwayContact Pathway Tissue Factor PathwayTissue Factor Pathway

Primary factor in DICPrimary factor in DIC

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Contact Tissue Factor + VIITissue Factor + VII

XIIIXIIIaa

XIIIXIII

ThrombinThrombin

FibrinFibrin(strong)(strong)

FibrinogenFibrinogen FibrinFibrin(weak)(weak)

IXIX

XIXI

XIXIaa

IXIXaa

XXaaVVaa

XIIXIIaa

ProthrombinProthrombin

TF-VIITF-VIIaa

(Prothrombinase)(Prothrombinase)

PLPL

PLPL(Tenase)(Tenase)

VIIIVIIIaa

PLPL

XX

Intrinsic Pathway

HKHKaa

Extrinsic Pathway

Common Pathway

TF Pathway

Coagulation PathwaysCoagulation Pathways

Protein C, ProteinS, Antithrombin III

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Anticlotting Mechanisms Antithrombin III (ATIII):Antithrombin III (ATIII):

The major inhibitor of the The major inhibitor of the coagulation cascade.coagulation cascade.

Inhibits ThrombinInhibits Thrombin Inhibits activated Factors IX, X, Inhibits activated Factors IX, X,

XI, and XII.XI, and XII. Activity is enhanced by heparin.Activity is enhanced by heparin.

Tissue factor pathway inhibitor Tissue factor pathway inhibitor TFPITFPI

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XIIIXIIIaa

XIIIXIII

ThrombinThrombin



IXIX

XIXI

XIXIaa

IXIXaa

XXaaVVaa

XIIXIIaa


TF-VIITF-VIIaa


PLPL

PLPL

(Tenase)(Tenase)

VIIIVIIIaa

PLPL

XX

Intrinsic Pathway

HKHKaa

Extrinsic Pathway

Common Pathway

TF Pathway



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Anticlotting Mechanisms

Protein CProtein C Activated by Activated by

Thrombin/ThrombomodulinThrombin/Thrombomodulin Anticoagulant and fibrinolytic Anticoagulant and fibrinolytic

activity.activity. Vitamin K and Protein S are Vitamin K and Protein S are

cofactorscofactors

Protein SProtein S

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XIIIXIIIaa

XIIIXIII

ThrombinThrombin



IXIX

XIXI

XIXIaa

IXIXaa

XXaaVVaa

XIIXIIaa


TF-VIITF-VIIaa


PLPL

PLPL

(Tenase)(Tenase)

VIIIVIIIaa

PLPL

XX

Intrinsic Pathway

HKHKaa

Extrinsic Pathway

Common Pathway

TF Pathway



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Fibrinolytic System PlasminPlasmin

Produced from Produced from Plasminogen by Tissue Plasminogen by Tissue Plasminogen activator Plasminogen activator (TPA)(TPA)

Degrades Fibrin and Degrades Fibrin and Fibrinogen (Fibrin Fibrinogen (Fibrin degradation products, degradation products, FDP)FDP)

Degrades Degrades Factors V, VIII, Factors V, VIII, IX, XI, and XII.IX, XI, and XII.

Activity is inhibited by Activity is inhibited by Antiplasmin.Antiplasmin.

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FibrinolysisFibrinolysisPlasminogen

Plasmin

Fibrin, fibrinogenFibrin, fibrinogen

ActivationActivationExtrinsic: t-PA,Extrinsic: t-PA, urokinase urokinase

Intrinsic: factor XIIa, HMWK,Intrinsic: factor XIIa, HMWK, kallikrein kallikrein

Exogenous:Exogenous: streptokinase streptokinase

Fibrin, fibrinogenFibrin, fibrinogendegradation productsdegradation products

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Fibrinolytic Inhibitors AntiplasminAntiplasmin

Inactivates plasmin rapidly.Inactivates plasmin rapidly. Acts slowly on plasmin Acts slowly on plasmin

sequestered in the fibrin clot.sequestered in the fibrin clot. Inactivates factors XI and XII Inactivates factors XI and XII

slowly.slowly.

Plasminogen -Activator Plasminogen -Activator Inhibitor-1(PAI-1)Inhibitor-1(PAI-1) Inhibits the function of TPAInhibits the function of TPA Also has some inhibitory Also has some inhibitory

activity against urokinase, activity against urokinase, plasmin, thrombin, activated plasmin, thrombin, activated Protein C, factors and XII, and Protein C, factors and XII, and kallikreinkallikrein

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FibrinolysisFibrinolysisPlasminogen

Plasmin

Fibrin, fibrinogenFibrin, fibrinogen

ActivationActivationExtrinsic: t-PA,Extrinsic: t-PA, urokinase urokinase

Intrinsic: factor XIIa, HMWK,Intrinsic: factor XIIa, HMWK, kallikrein kallikrein

Exogenous:Exogenous: streptokinase streptokinase

Fibrin, fibrinogenFibrin, fibrinogendegradation productsdegradation products

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Hemostatic Balance

ATIIIClotting Factors

Tissue factor*

PAI-1

AntiplasminTFPI

Prot. C

Prot. S

ProcoagulantProcoagulant AnticoagulantAnticoagulant

Fibrinolytic System

DIC

An acquired syndrome An acquired syndrome characterized by characterized by systemicsystemic intravascularintravascular coagulationcoagulation

Coagulation is Coagulation is alwaysalways the the initial eventinitial event

SYSTEMIC ACTIVATION OF COAGULATION

Intravascular deposition of

fibrin

Depletion of platelets and coagulation

factors

Thrombosis of small and midsize

vesselsBleeding

Organ failure DEATHDEATH

Pathophysiology of DIC

Activation of Blood CoagulationActivation of Blood Coagulation Suppression of Physiologic Anticoagulant Suppression of Physiologic Anticoagulant

PathwaysPathways Impaired FibrinolysisImpaired Fibrinolysis CytokinesCytokines


Activation of Blood CoagulationActivation of Blood Coagulation Tissue factor/factor VIIa mediated thrombin generation via the Tissue factor/factor VIIa mediated thrombin generation via the

extrinsic pathwayextrinsic pathway complex activates factor IX and Xcomplex activates factor IX and X

TF TF endothelial cellsendothelial cells monocytesmonocytes Extravascular:Extravascular:

• lunglung

• kidneykidney

• epithelial cellsepithelial cells


Suppression of Physiologic Anticoagulant Suppression of Physiologic Anticoagulant PathwaysPathways reduced antithrombin III levels reduced antithrombin III levels reduced activity of the protein C-protein S systemreduced activity of the protein C-protein S system Insufficient regulation of tissue factor activity by Insufficient regulation of tissue factor activity by

tissue factor pathway inhibitor (TFPI)tissue factor pathway inhibitor (TFPI) inhibits TF/FVIIa/Fxa complex activity inhibits TF/FVIIa/Fxa complex activity

Pathophysiology of DIC Impaired FibrinolysisImpaired Fibrinolysis

relatively suppressed at time of maximal activation of relatively suppressed at time of maximal activation of coagulation due to increased plasminogen activator inhibitor coagulation due to increased plasminogen activator inhibitor type 1type 1

Pathophysiology of DIC - Cytokines

CytokinesCytokines IL-6, and IL-1 mediates coagulation activation in DICIL-6, and IL-1 mediates coagulation activation in DIC TNF-TNF-

mediates dysregulation of physiologic anticoagulant pathways and mediates dysregulation of physiologic anticoagulant pathways and fibrinolysisfibrinolysis

modulates IL-6 activitymodulates IL-6 activity

IL-10 may modulate the activation of coagulationIL-10 may modulate the activation of coagulation

CoagulationInflamation

Diagnosis of DIC

Presence of disease associated with DICPresence of disease associated with DIC Appropriate clinical settingAppropriate clinical setting

Clinical evidence of thrombosis, hemorrhage or both.Clinical evidence of thrombosis, hemorrhage or both. Laboratory studiesLaboratory studies

no single test is accurateno single test is accurate serial test are more helpful than single testserial test are more helpful than single test

Conditions Associated With DIC

MalignancyMalignancy LeukemiaLeukemia Metastatic diseaseMetastatic disease

CardiovascularCardiovascular Post cardiac arrestPost cardiac arrest Acute MIAcute MI Prosthetic devicesProsthetic devices

Hypothermia/HyperthermiaHypothermia/Hyperthermia

PulmonaryPulmonary ARDS/RDSARDS/RDS Pulmonary embolismPulmonary embolism

Severe acidosisSevere acidosis Severe anoxiaSevere anoxia Collagen vascular diseaseCollagen vascular disease AnaphylaxisAnaphylaxis

Conditions Associated With DIC

Infectious/SepticemiaInfectious/Septicemia BacterialBacterial

Gm - / Gm +Gm - / Gm +

ViralViral CMVCMV VaricellaVaricella HepatitisHepatitis

FungalFungal

Intravascular hemolysisIntravascular hemolysis Acute Liver DiseaseAcute Liver Disease

Tissue InjuryTissue Injury traumatrauma extensive surgeryextensive surgery tissue necrosistissue necrosis head traumahead trauma

ObstetricObstetric Amniotic fluid emboliAmniotic fluid emboli Placental abruptionPlacental abruption EclampsiaEclampsia Missed abortionMissed abortion

Clinical Manifestations of DIC

ORGAN ISCHEMIC HEMOR.Skin Pur. Fulminans

GangreneAcral cyanosis

PetechiaeEchymosisOozing

CNS Delirium/ComaInfarcts

Intracranialbleeding

Renal Oliguria/AzotemiaCortical Necrosis

Hematuria

Cardiovascular MyocardialDysfxn

Pulmonary Dyspnea/HypoxiaInfarct

Hemorrhagiclung

GIEndocrine

Ulcers, InfarctsAdrenal infarcts

Massivehemorrhage.

Ischemic Findingsare earliest!

Bleeding is the most obvious

clinical finding

Clinical Manifestations of DIC

Microscopic findings in DIC

FragmentsFragments SchistocytesSchistocytes Paucity of plateletsPaucity of platelets

Laboratory Tests Used in DIC

D-dimerD-dimer** Antithrombin IIIAntithrombin III* * F. 1+2*F. 1+2* Fibrinopeptide A*Fibrinopeptide A* Platelet factor 4*Platelet factor 4* Fibrin Degradation ProdFibrin Degradation Prod Platelet countPlatelet count Protamine testProtamine test

Thrombin timeThrombin time FibrinogenFibrinogen Prothrombin timeProthrombin time Activated PTTActivated PTT Protamine testProtamine test Reptilase timeReptilase time Coagulation factor levelsCoagulation factor levels

*Most reliable test*Most reliable test

Laboratory diagnosis ThrombocytopeniaThrombocytopenia

plat count <100,000 or rapidly decliningplat count <100,000 or rapidly declining Prolonged clotting times (PT, APTT)Prolonged clotting times (PT, APTT) Presence of Fibrin degradation products or positive Presence of Fibrin degradation products or positive

D-dimerD-dimer Low levels of coagulation inhibitorsLow levels of coagulation inhibitors

AT III, protein CAT III, protein C Low levels of coagulation factorsLow levels of coagulation factors

Factors V,VIII,X,XIIIFactors V,VIII,X,XIII Fibrinogen levels Fibrinogen levels notnot useful diagnostically useful diagnostically

Differential Diagnosis

Severe liver failureSevere liver failure Vitamin K deficiencyVitamin K deficiency Liver diseaseLiver disease Thrombotic thrombocytopenic purpuraThrombotic thrombocytopenic purpura Congenital abnormalities of fibrinogenCongenital abnormalities of fibrinogen HELLP syndromeHELLP syndrome

Treatment of DIC

Stop the triggering processStop the triggering process . . The only proven treatment!The only proven treatment!

Supportive therapySupportive therapy No specific treatmentsNo specific treatments

Plasma and platelet substitution therapyPlasma and platelet substitution therapy AnticoagulantsAnticoagulants Physiologic coagulation inhibitorsPhysiologic coagulation inhibitors

Plasma therapy IndicationsIndications

Active bleedingActive bleeding Patient requiring invasive proceduresPatient requiring invasive procedures Patient at high risk for bleeding complicationsPatient at high risk for bleeding complications

Prophylactic therapy has no proven benefit.Prophylactic therapy has no proven benefit. Cons:Cons: Fresh frozen plasma(FFP):Fresh frozen plasma(FFP):

provides clotting factors, fibrinogen, inhibitors, and platelets in provides clotting factors, fibrinogen, inhibitors, and platelets in balanced amounts.balanced amounts.

Usual dose is 10-15 ml/kgUsual dose is 10-15 ml/kg

Platelet therapy

IndicationsIndications Active bleedingActive bleeding Patient requiring invasive proceduresPatient requiring invasive procedures Patient at high risk for bleeding complicationsPatient at high risk for bleeding complications

PlateletsPlatelets approximate dose 1 unit/10kgapproximate dose 1 unit/10kg

Blood

Replaced as needed to maintain adequate oxygen Replaced as needed to maintain adequate oxygen delivery.delivery. Blood loss due to bleedingBlood loss due to bleeding RBC destruction (hemolysis)RBC destruction (hemolysis)

Coagulation Inhibitor Therapy

Antithrombin IIIAntithrombin III Protein C concentrateProtein C concentrate Tissue Factor Pathway Inhibitor (TFPI)Tissue Factor Pathway Inhibitor (TFPI) HeparinHeparin

The major inhibitor of the coagulation cascadeThe major inhibitor of the coagulation cascade Levels are decreased in DIC.Levels are decreased in DIC. Anticoagulant and antiinflammatory propertiesAnticoagulant and antiinflammatory properties

Therapeutic goal is to achieve supranormal levels of ATIII (>125-150%).Therapeutic goal is to achieve supranormal levels of ATIII (>125-150%). Experimental data indicated a beneficial effect in preventing or attenuating DIC in Experimental data indicated a beneficial effect in preventing or attenuating DIC in

septic shockseptic shock reduced DIC scores, DIC duration, and some improvement in organ functionreduced DIC scores, DIC duration, and some improvement in organ function

Clinical trials have shown laboratory evidence of attenuation of DIC and trends Clinical trials have shown laboratory evidence of attenuation of DIC and trends toward improved outcomes.toward improved outcomes.

A clear benefit has not been established in clinical trialsA clear benefit has not been established in clinical trials..

Antithrombin III

Protein C Concentrates

Inhibits Factor Va, VIIa and PAI-1 in conjunction with Inhibits Factor Va, VIIa and PAI-1 in conjunction with thrombomodulin.thrombomodulin.

Protein S is a cofactorProtein S is a cofactor Therapeutic use in DIC is experimental and is based on studies Therapeutic use in DIC is experimental and is based on studies

that show:that show: Patients with congenital deficiency are prone to thromboembolic disease.Patients with congenital deficiency are prone to thromboembolic disease. Protein C levels are low in DIC due to sepsis.Protein C levels are low in DIC due to sepsis. Levels correlate with outcome.Levels correlate with outcome. Clinical trials show significantly decreased morbidity and mortality in Clinical trials show significantly decreased morbidity and mortality in

DIC due to sepsis.DIC due to sepsis.

Tissue Factor Pathway Inhibitor

Tissue factor is expressed on endothelial cells and Tissue factor is expressed on endothelial cells and macrophagesmacrophages

TFPI complexes with TF, Factor VIIa,and Factor Xa to TFPI complexes with TF, Factor VIIa,and Factor Xa to inhibit generation of thrombin from prothrombininhibit generation of thrombin from prothrombin

TF inhibition may also have antiinflammatory effectsTF inhibition may also have antiinflammatory effects Clinical studies using recombinant TFPI are promising.Clinical studies using recombinant TFPI are promising.

Heparin

Use is very controversial. Data is mixed.Use is very controversial. Data is mixed. May be indicated in patients with clinical evidence May be indicated in patients with clinical evidence

of fibrin deposition or significant thrombosis.of fibrin deposition or significant thrombosis. Generally contraindicated in patients with Generally contraindicated in patients with

significant bleeding and CNS insults.significant bleeding and CNS insults. Dosing and route of administration varies.Dosing and route of administration varies. Requires normal levels of ATIII.Requires normal levels of ATIII.

Antifibrinolytic Therapy

Rarely indicated in DICRarely indicated in DIC Fibrinolysis is needed to clear thrombi from the micro circulation.Fibrinolysis is needed to clear thrombi from the micro circulation. Use can lead to fatal disseminated thrombosis.Use can lead to fatal disseminated thrombosis.

May be indicated for May be indicated for life threateninglife threatening bleeding under the bleeding under the following conditions:following conditions: bleeding has not responded to other therapies and:bleeding has not responded to other therapies and: laboratory evidence of overwhelming fibrinolysis.laboratory evidence of overwhelming fibrinolysis. evidence that the intravascular coagulation has ceased.evidence that the intravascular coagulation has ceased.

Agents: tranexamic acid, EACAAgents: tranexamic acid, EACA

Summary

DIC is a syndrome characterized DIC is a syndrome characterized systemic intravascular systemic intravascular coagulation.coagulation.

Coagulation is the initial event and the extent of intravascular Coagulation is the initial event and the extent of intravascular thrombosis has the greatest impact on morbidity and mortality.thrombosis has the greatest impact on morbidity and mortality.

Important link between inflammation and coagulation. Important link between inflammation and coagulation. Morbidity and mortality remain high.Morbidity and mortality remain high. The only proven treatment is reversal or control of the The only proven treatment is reversal or control of the

underlying cause.underlying cause.

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Disseminated Intravascular Coagulation Keith Lewis, MD