CONTROL OF HEMOSTASIS Jerrold H. Levy, MD Professor of Anesthesiology Deputy Chair for Research Emory University School of Medicine Division of Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia

SIMPLIFIED CLINICIAN’S VIEW OF HEMOSTASIS Platelet/coagulation factor activation Lots of exciting biochemistry CLOT

COMPONENTS OF HEMOSTASIS n Vasculature n Coagulation proteins n Platelets

Hemostasis Subendothelial matrix Platelets Hemostatic plug Fibrin Endothelial cell RBC WBC WBC

5 COAGULATION PATHWAYS

Contact Tissue Factor + VII XIII a XIII Thrombin Fibrin(strong) Fibrinogen Fibrin(weak) IX XI XI a IX a XaXaXaXa VaVaVaVa XII a Prothrombin TF-VII a (Prothrombinase) PL PL (Tenase) VIII a PL X Intrinsic Pathway HK a Extrinsic Pathway Common Pathway TF Pathway Coagulation Pathways Protein C, Protein S, Antithrombin III

Hoffman et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61. TF-Bearing Cell Activated Platelet Platelet TF VIIIa Va VIIIa Va Va VIIa TF VIIa Xa X II IIa IX VVa II VIII/vWF VIIIa II IXa X IX X IXa IXa VIIa Xa IIa IIa Xa Normal Hemostasis: Pivotal role of TF/VIIa

8 PLATELET ACTIVATION PATHWAYS

Adhesion GpIIb/IIIa Platelet Activation Pathways (1) GpIIb/IIIa Aggregation ADP Adrenaline Platelet GpIb Exposed Collagen Endothelium vWF COLLAGEN GpIIb/IIIa Aggregation GpIIb/IIIa Aggregation Adhesion ADP Adrenaline THROMBIN

Platelet Activation Pathways (2) Platelet Aggregation Fibrinogen TxA 2 Fibrinogen Binding Site ADP Thrombin Platelet Herbert. Exp Opin Invest Drugs 1994;3:

CLOT FORMATION Fibrin Red Blood Cell Platelet

Fibrinolysis Plasminogen Plasmin Fibrin, fibrinogen Activation Extrinsic: t-PA, urokinase Intrinsic: factor XIIa, HMWK, kallikrein Exogenous: streptokinase Fibrin, fibrinogen degradation products

13FIBRINOLYSIS

Fibrinolysis

15 CONDITIONS PRODUCING COAGULOPATHY

Conditions of coagulopathy   Hemophilia   Platelet disorders   Liver disease   DIC   Dilution coagulopathy   Anticoagulant 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)

18 HEMOSTASIS: ROLE OF FACTOR VII and TISSUE FACTOR

TF-Bearing Cell Activated Platelet Platelet TF Va Va TF VIIa Xa X II IIa VVa II X IIa Xa VIIa FVIIa Mechanism of Action Hoffman et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61.

FACTOR VIIa Mechanism of Action Increases the tissue factor (TF) occupancyIncreases the tissue factor (TF) occupancy In pharmacological doses binds to activated plateletsIn pharmacological doses binds to activated platelets Activates Factor X independent of tissue factorActivates Factor X independent of tissue factor Proceedings of the National Academy of Sciences 97(10): , Circulation. 103(21):2555-9, Blood Coagulation & Fibrinolysis. 11 Suppl 1:S107-11, Proceedings of the National Academy of Sciences. 96(16): , Haemostasis. 30 Suppl 2:41-7, Thrombosis Research. 98(4):311-21, 2000.

21 CONTACT ACTIVATION AND CARDIOPULMONARY BYPASS

Contact Activation of Blood Proteins Blood/Surface Interaction ThrombinPlasminKallikrein ClottingFibrinolysisKinins Platelets White Cells Systemic Inflammatory Response Cytokines/Adhesion Molecules Serine Protease Inhibitors Heparin Complement

Negative Charged Surface XII FXIIa Bradykinin Thrombin Generation XIa XII FXIIa FXI HK PKK HK FXIIa Kallikrein XII Kallikrein FXIIa PKK HK Contact Activation - The Role of Kallikrein

KininGeneration AngiotensinSystem ComplementSystem HMW-Kininogen Bradykinin Renin Prorenin C1C1C1C1 Prekallikrein Factor XIIa Factor XII Factor XIIa Factor XII Factor XIa Factor XI Coagulation System System Plasmin Plasminogen FibrinolyticSystem C1C1C1C1_Kallikrein

25 ANTICOAGULANTS/ ANTITHROMBINS

ANTITHROMBINS/ ANTICOAGULANTS n Argatroban n Bivalirudin (Angiomax) n Hirudin: r-lepirudin, (Refludan) n Low molecular weight heparin (LMWH)/Xa inhibitors n Warfarin Levy JH: Novel IV antithrombins. Am Heart J 2001:141:1043

LMWH n Anti-Xa activity greater than AT activity, purified from UFH, MWt n Long duration of action, not reversible with protamine n Included enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep)

Thrombin Inactivation: Heparin Pentasaccharidesequence Heparin/ATIII/IIa Ternary complex accelerates inactivation of IIa by ATIII LMW Heparin/ATIII No acceleration of inactivation of IIa by ATIII without ternary complex IIa ATIII IIa Pentasaccharidesequence

Factor Xa Inactivation: LMWH/Heparin Heparin/ATIII Ternary complex not necessary to accelerate inactivation of Xa by ATIII Xa ATIII LMW Heparin/ATIII Ternary complex not necessary to accelerate inactivation of Xa by ATIII Pentasaccharidesequence Xa ATIII

LMWH—Clinical Applications n Prevention of DVT/PE u In patients undergoing hip replacement, during & following hospitalization u In patients undergoing knee replacement u In patients undergoing abdominal surgery who are at risk of TE complications n Treatment of DVT/PE n Ischemic complications of unstable angina and non-Q wave MI

Biological Consequences of Reduced Binding of LMWH to Proteins and Cells Binding TargetBiological EffectsClinical Consequences ThrombinReduced anti-IIa toUnknown anti-Xa ratio ProteinsMore predictableMonitoring of anticoagulant anticoagulant responseeffect unnecessary MacrophagesCleared through renalLonger plasma half-life; mechanismonce daily subcutaneous treatment effective PlateletsReduced incidence ofReduced incidence of heparin-dependentheparin-induced antibodythrombocytopenia OsteoblastsReduced activation ofLower incidence of osteoclastsosteopenia Dalen JE, Hirsh J. Fifth ACCP Consensus Conference on Antithrombotic Therapy. Chest 1998;114: 501s

n LMWH u Bleeding u Thrombocytopeni a u Hypersensitivity Heparin/LMWH—Adverse Effects n Heparin u Bleeding u Thrombocytopeni a u Osteoporosis u Hypersensitivity

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

Warfarin—Mechanism of Action Vitamin K Warfarin Synthesis of Dysfunctional Coagulation Factors VII IX X II Vitamin K Utilization Reduced

Warfarin—Indications n Prophylaxis and/or treatment of: u Venous thrombosis and its extension u Pulmonary embolism n Thromboembolic complications associated with AF and/or cardiac valve replacement n Reduce risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MI

Elimination Half-Lives of Vitamin K-Dependent Proteins ProteinHalf-Life Factor VII4–6 hours Factor IX24 hours Factor II60 hours Factor X48–72 hours Protein C8 hours Protein S30 hours

Warfarin—Contraindications n Risk of hemorrhage is greater than benefits of therapy n Pregnancy n Hemorrhagic tendencies or blood dyscrasias n Traumatic surgery with large open areas, recent or contemplated surgery of CNS or eye n Bleeding tendencies with active ulceration or overt bleeding n Senility, alcoholism, psychosis or other lack of patient cooperation n Spinal puncture and procedures with potential for uncontrollable bleeding n Inadequate laboratory facilities

Warfarin—Adverse Effects n Fatal or non-fatal hemorrhage from any tissue or organ n Necrosis of skin and other tissues n Other adverse reactions reported less frequently include: u Systemic cholesterol microembolization u Alopecia u Purple toes syndrome, urticaria, dermatitis including bullous eruptions

39LOVE=HEMOSTASIS Everybody talks about it, nobody understands it. JH Levy 2000