CONTROL OF CONTROL OF HEMOSTASISHEMOSTASIS

Jerrold H. Levy, MDJerrold H. Levy, MDProfessor of AnesthesiologyProfessor of AnesthesiologyDeputy Chair for ResearchDeputy Chair for Research

Emory University School of MedicineEmory University School of MedicineDivision of Cardiothoracic Anesthesiology and Division of Cardiothoracic Anesthesiology and

Critical CareCritical CareEmory HealthcareEmory HealthcareAtlanta, GeorgiaAtlanta, Georgia

SIMPLIFIED CLINICIAN’S VIEW OF SIMPLIFIED CLINICIAN’S VIEW OF HEMOSTASISHEMOSTASIS

Platelet/coagulation factor activationPlatelet/coagulation factor activation

Lots of exciting biochemistryLots of exciting biochemistry

CLOTCLOT

COMPONENTS OF COMPONENTS OF HEMOSTASISHEMOSTASIS

VasculatureVasculatureCoagulation proteinsCoagulation proteinsPlateletsPlatelets

HemostasisHemostasis

Subendothelial matrixSubendothelial matrix

PlateletsPlatelets

Hemostatic plugHemostatic plug

FibrinFibrin

Endothelial cellEndothelial cell

RBCRBCWBCWBC

WBCWBC

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COAGULATION COAGULATION PATHWAYSPATHWAYS

Contact Tissue Factor + VIITissue Factor + VII

XIIIXIIIaa

XIIIXIII

ThrombinThrombin

FibrinFibrin(strong)(strong)

FibrinogenFibrinogen FibrinFibrin(weak)(weak)

IXIX

XIXI

XIXIaa

IXIXaa

XXaaVVaa

XIIXIIaaProthrombinProthrombin

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, Protein S, Antithrombin III

Hoffman et al. Hoffman et al. Blood Coagul FibrinolysisBlood Coagul Fibrinolysis 1998;9(suppl 1):S61. 1998;9(suppl 1):S61.

TF-Bearing CellTF-Bearing Cell

Activated PlateletActivated Platelet

PlateletPlatelet

TFTF

VIIIaVIIIa VaVa

VIIIaVIIIa VaVa

VaVa

VIIaVIIa

TFTF VIIaVIIa XaXa

XX IIIIIIaIIa

IXIXVV VaVa

IIII

VIII/vWFVIII/vWF

VIIIaVIIIa

IIII

IXaIXa

XXIXIX

XX

IXaIXa

IXaIXaVIIaVIIaXaXa

IIaIIa

IIaIIa

XaXa

Normal Hemostasis: Pivotal role of TF/VIIaNormal Hemostasis: Pivotal role of TF/VIIa

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PLATELET PLATELET ACTIVATION ACTIVATION PATHWAYSPATHWAYS

Adhesion

GpIIb/IIIa

Platelet Activation Pathways (1)Platelet Activation Pathways (1)

GpIIb/IIIaGpIIb/IIIa Aggregation

ADP

Adrenaline Platelet GpIb

Exposed Collagen

Endothelium

vWF

COLLAGEN

GpIIb/IIIaGpIIb/IIIa AggregationGpIIb/IIIaGpIIb/IIIa Aggregation

AdhesionAdhesion

ADP

Adrenaline

THROMBINTHROMBIN

Platelet Activation Pathways (2)Platelet Activation Pathways (2)

Platelet AggregationPlatelet Aggregation

FibrinogenFibrinogen

TxATxA22

Fibrinogen Binding SiteFibrinogen Binding Site

ADPADP ThrombinThrombin

PlateletPlatelet

Herbert. Exp Opin Invest Drugs 1994;3:449-455.Herbert. Exp Opin Invest Drugs 1994;3:449-455.

CLOT FORMATIONCLOT FORMATION

FibrinFibrin

Red Blood CellRed Blood Cell

PlateletPlatelet

FibrinolysisFibrinolysisPlasminogen

Plasmin

Fibrin, fibrinogenFibrin, fibrinogen

ActivationActivationExtrinsic: t-PA, urokinaseExtrinsic: t-PA, urokinase

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

Exogenous: streptokinaseExogenous: streptokinase

Fibrin, fibrinogenFibrin, fibrinogendegradation productsdegradation products

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FIBRINOLYSISFIBRINOLYSIS

FibrinolysisFibrinolysis

Plasmin

t-PA

PG

PG

PL

t-PA

Plasmin

t-PA

PG

t-PAPG

PLFDPs

Plasminogen

Fibrin

FDPs

Plasminogen

FibrinFibrin

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CONDITIONS CONDITIONS PRODUCING PRODUCING

COAGULOPATHYCOAGULOPATHY

Conditions of coagulopathy

HemophiliaPlatelet disordersLiver diseaseDICDilution coagulopathyAnticoagulant treatment

CAUSES OF COAGULOPATHY in LIVER DISEASE

Decreased coagulation factors II, VII, IX, and X synthesis

Fibrinolysis Platelet dysfunction Decreased physiologic anticoagulant synthesis (AT III, Protein C and S)

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HEMOSTASIS: HEMOSTASIS: ROLE OF FACTOR ROLE OF FACTOR

VII and TISSUE VII and TISSUE FACTORFACTOR

TF-Bearing CellTF-Bearing Cell

Activated PlateletActivated Platelet

PlateletPlateletTFTF

VaVa

VaVaTFTF VIIaVIIa XaXa

XX IIIIIIaIIa

VV VaVa

IIIIXX

IIaIIaXaXaVIIaVIIa

FVIIa Mechanism of ActionFVIIa Mechanism of Action

Hoffman et al. Hoffman et al. Blood Coagul FibrinolysisBlood Coagul Fibrinolysis 1998;9(suppl 1):S61. 1998;9(suppl 1):S61.

FACTOR VIIa Mechanism of Action

• Increases the tissue factor (TF) Increases the tissue factor (TF) occupancyoccupancy

• In pharmacological doses binds to In pharmacological doses binds to activated plateletsactivated platelets

• Activates Factor X independent of Activates Factor X independent of tissue factortissue factor

Proceedings of the National Academy of Sciences 97(10):5255-60, 2000. Circulation. 103(21):2555-9, 2001. Blood Coagulation & Fibrinolysis. 11 Suppl 1:S107-11, 2000.

Proceedings of the National Academy of Sciences. 96(16):8925-30, 1999.Haemostasis. 30 Suppl 2:41-7, 2000. Thrombosis Research. 98(4):311-21, 2000.

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CONTACT ACTIVATION CONTACT ACTIVATION AND AND

CARDIOPULMONARY CARDIOPULMONARY BYPASSBYPASS

Contact Activation of Blood Contact Activation of Blood ProteinsProteins

Blood/Surface InteractionBlood/Surface Interaction

Thrombin Plasmin Kallikrein

Clotting Fibrinolysis Kinins

Platelets White Cells

Systemic Inflammatory Response

Cytokines/Adhesion Molecules

Serine Protease InhibitorsHeparin

Complement

Negative Charged SurfaceNegative Charged SurfaceXII

FXIIa

BradykininBradykinin

Thrombin GenerationThrombin Generation

XIa

XII

FXIIa

FXI

HK

PKK

HK

FXIIa

Kallikrein

XII

Kallikrein

FXIIa

PKK

HK

Contact Activation - The Role of KallikreinContact Activation - The Role of Kallikrein

Kinin Kinin GenerationGeneration

AngiotensinAngiotensinSystemSystem

ComplementComplementSystemSystem

HMW-KininogenHMW-Kininogen

BradykininBradykinin

Renin Renin

ProreninProrenin

CC11

PrekallikreinPrekallikreinFactor XIIaFactor XIIa

Factor XIIFactor XII

Factor XIIaFactor XIIa

Factor XIIFactor XII

Factor XIaFactor XIa

Factor XIFactor XI

CoagulationCoagulation SystemSystem

PlasminPlasminogenPlasminogenFibrinolyticFibrinolytic

SystemSystem

CC11

__

KallikreinKallikrein

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ANTICOAGULANTS/ANTICOAGULANTS/ANTITHROMBINSANTITHROMBINS

ANTITHROMBINS/ANTITHROMBINS/ANTICOAGULANTSANTICOAGULANTS ArgatrobanArgatroban Bivalirudin (Angiomax)Bivalirudin (Angiomax) Hirudin: r-lepirudin, (Refludan)Hirudin: r-lepirudin, (Refludan) Low molecular weight heparin Low molecular weight heparin

(LMWH)/Xa inhibitors(LMWH)/Xa inhibitors WarfarinWarfarinLevy JH: Novel IV antithrombins. Am Heart J 2001:141:1043Levy JH: Novel IV antithrombins. Am Heart J 2001:141:1043

LMWHLMWH Anti-Xa activity greater than AT Anti-Xa activity greater than AT

activity, purified from UFH, MWt activity, purified from UFH, MWt 4500-60004500-6000

Long duration of action, not Long duration of action, not reversible with protaminereversible with protamine

Included enoxaparin (Lovenox), Included enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin dalteparin (Fragmin), tinzaparin (Innohep)(Innohep)

Thrombin Inactivation: HeparinThrombin Inactivation: Heparin

PentasaccharidePentasaccharidesequencesequence

Heparin/ATIII/IIaHeparin/ATIII/IIaTernary complex accelerates Ternary complex accelerates inactivation of IIa by ATIIIinactivation of IIa by ATIII

LMW Heparin/ATIIILMW Heparin/ATIIINo acceleration of No acceleration of inactivation of IIa by ATIII inactivation of IIa by ATIII without ternary complexwithout ternary complex

IIaIIa

ATIII IIaIIa

ATIII

PentasaccharidePentasaccharidesequencesequence

Factor Xa Inactivation: LMWH/HeparinFactor Xa Inactivation: LMWH/Heparin

Heparin/ATIIIHeparin/ATIIITernary complex not Ternary complex not necessary to accelerate necessary to accelerate inactivation of Xa by ATIIIinactivation of Xa by ATIII

XaXaATIII

LMW Heparin/ATIIILMW Heparin/ATIIITernary complex not Ternary complex not necessary to accelerate necessary to accelerate inactivation of Xa by ATIIIinactivation of Xa by ATIII

PentasaccharidePentasaccharidesequencesequence

XaXa ATIII

LMWH—Clinical ApplicationsLMWH—Clinical Applications

Prevention of DVT/PEPrevention of DVT/PE In patients undergoing hip replacement, during & following In patients undergoing hip replacement, during & following

hospitalizationhospitalization

In patients undergoing knee replacementIn patients undergoing knee replacement

In patients undergoing abdominal surgery who are at risk of TE In patients undergoing abdominal surgery who are at risk of TE complicationscomplications

Treatment of DVT/PETreatment of DVT/PE

Ischemic complications of unstable angina and non-Q wave MIIschemic complications of unstable angina and non-Q wave MI

Biological Consequences of Reduced Binding Biological Consequences of Reduced Binding of LMWH to Proteins and Cellsof LMWH to Proteins and Cells

Binding TargetBinding Target Biological EffectsBiological Effects Clinical ConsequencesClinical ConsequencesThrombinThrombin Reduced anti-IIa toReduced anti-IIa to UnknownUnknown

anti-Xa ratioanti-Xa ratioProteinsProteins More predictableMore predictable Monitoring of anticoagulantMonitoring of anticoagulant

anticoagulant responseanticoagulant response effect unnecessaryeffect unnecessaryMacrophagesMacrophages Cleared through renalCleared through renal Longer plasma half-life;Longer plasma half-life;

mechanismmechanism once daily subcutaneousonce daily subcutaneoustreatment effectivetreatment effective

PlateletsPlatelets Reduced incidence ofReduced incidence of Reduced incidence ofReduced incidence ofheparin-dependentheparin-dependent heparin-inducedheparin-inducedantibodyantibody thrombocytopeniathrombocytopenia

OsteoblastsOsteoblasts Reduced activation ofReduced activation of Lower incidence ofLower incidence ofosteoclastsosteoclasts osteopeniaosteopenia

Dalen JE, Hirsh J. Fifth ACCP Consensus Conference onDalen JE, Hirsh J. Fifth ACCP Consensus Conference onAntithrombotic Therapy. Chest 1998;114: 501sAntithrombotic Therapy. Chest 1998;114: 501s

LMWHLMWH BleedingBleeding ThrombocytopeniaThrombocytopenia HypersensitivityHypersensitivity

Heparin/LMWH—Adverse EffectsHeparin/LMWH—Adverse Effects

HeparinHeparin BleedingBleeding ThrombocytopeniaThrombocytopenia OsteoporosisOsteoporosis HypersensitivityHypersensitivity

Adapted from the black box warning of LMWHAdapted from the black box warning of LMWH

LMWH—Special PrecautionsLMWH—Special PrecautionsWhen neuroaxial anesthesia (epidural/spinal anesthesia) or When neuroaxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with LMWHs for prevention of scheduled to be anticoagulated with LMWHs for prevention of thromboembolic complications are at risk of developing an thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or epidural or spinal hematoma which can result in long-term or permanent paralysis.permanent paralysis.Risk of these events is increased by the use of indwelling Risk of these events is increased by the use of indwelling epidural catheters or concomitant use of NSAIDs, platelet epidural catheters or concomitant use of NSAIDs, platelet inhibitors, or other anticoagulants.inhibitors, or other anticoagulants.Patients should be frequently monitored for signs and symptoms Patients should be frequently monitored for signs and symptoms of neurological impairment.of neurological impairment.

Warfarin—Mechanism of ActionWarfarin—Mechanism of Action

Vitamin KVitamin K

WarfarinWarfarin

Synthesis of Synthesis of Dysfunctional Dysfunctional Coagulation Coagulation

FactorsFactors

VIIVII

IXIX

XX

IIII

Vitamin K Utilization Reduced

Warfarin—IndicationsWarfarin—Indications

Prophylaxis and/or treatment of:Prophylaxis and/or treatment of: Venous thrombosis and its extensionVenous thrombosis and its extension Pulmonary embolismPulmonary embolism

Thromboembolic complications associated with AF Thromboembolic complications associated with AF and/or cardiac valve replacementand/or cardiac valve replacement

Reduce risk of death, recurrent MI, and thromboembolic Reduce risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MIevents such as stroke or systemic embolization after MI

Elimination Half-Lives of Elimination Half-Lives of Vitamin K-Dependent ProteinsVitamin K-Dependent Proteins

ProteinProtein Half-LifeHalf-Life

Factor VIIFactor VII 4–6 hours4–6 hours

Factor IXFactor IX 24 hours24 hours

Factor IIFactor II 60 hours60 hours

Factor XFactor X 48–72 hours48–72 hours

Protein CProtein C 8 hours8 hours

Protein SProtein S 30 hours30 hours

Warfarin—ContraindicationsWarfarin—Contraindications

Risk of hemorrhage is greater than benefits of therapyRisk of hemorrhage is greater than benefits of therapy PregnancyPregnancy Hemorrhagic tendencies or blood dyscrasiasHemorrhagic tendencies or blood dyscrasias Traumatic surgery with large open areas, recent or Traumatic surgery with large open areas, recent or

contemplated surgery of CNS or eyecontemplated surgery of CNS or eye Bleeding tendencies with active ulceration or overt bleedingBleeding tendencies with active ulceration or overt bleeding Senility, alcoholism, psychosis or other lack of patient Senility, alcoholism, psychosis or other lack of patient

cooperationcooperation Spinal puncture and procedures with potential for Spinal puncture and procedures with potential for

uncontrollable bleedinguncontrollable bleeding Inadequate laboratory facilitiesInadequate laboratory facilities

Warfarin—Adverse EffectsWarfarin—Adverse Effects

Fatal or non-fatal hemorrhage from any tissue or Fatal or non-fatal hemorrhage from any tissue or organorgan

Necrosis of skin and other tissuesNecrosis of skin and other tissues Other adverse reactions reported less frequently Other adverse reactions reported less frequently

include:include: Systemic cholesterol microembolizationSystemic cholesterol microembolization AlopeciaAlopecia Purple toes syndrome, urticaria, dermatitis including Purple toes syndrome, urticaria, dermatitis including

bullous eruptionsbullous eruptions

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LOVE=HEMOSTASISLOVE=HEMOSTASISEverybody talks Everybody talks about it, nobody about it, nobody understands it.understands it.

JH Levy 2000JH Levy 2000