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 CLINICIANS VIEW OF HEMOSTASIS

Platelet/coagulation factor activation Lots of exciting biochemistry

CLOT

COMPONENTS OF HEMOSTASIS
Vasculature Coagulation

proteins

Platelets

Hemostasis
Subendothelial matrix Hemostatic plug

WBC

Platelets

Endothelial cell WBC Fibrin RBC

COAGULATION PATHWAYS

Coagulation Pathways
Intrinsic Pathway Contact Extrinsic Pathway

IX

TF Pathway

XI XIIa HKa XIa IXa

TF-VIIa
PL PL VIIIa
(Tenase)

Tissue Factor + VII X

Common Pathway

Prothrombin PL Va Thrombin Fibrinogen XIII

Xa
(Prothrombinase)

Protein C, Protein S, Antithrombin III

Fibrin
(weak)

XIIIa

(strong)

Fibrin

Normal Hemostasis: Pivotal role of TF/VIIa

X TF

II
VIII/vWF Xa Va IIa VIIIa V Va Platelet

VIIa

TF-Bearing Cell TF VIIa IXa IXa

IX X

II
Xa

VIIa
IX

Va Activated Platelet Va IXa VIIIa Xa X

VIIIa

IIa IIa

II

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

PLATELET ACTIVATION PATHWAYS

Platelet Activation Pathways (1)

COLLAGEN

THROMBIN
ADP
GpIIb/IIIa GpIIb/IIIa

GpIIb/IIIa

Aggregation

Adrenaline

Platelet

Adhesion
vWF

Endothelium
Exposed Collagen

Platelet Activation Pathways (2)

Thrombin

Platelet
Fibrinogen Binding Site

Fibrinogen

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

CLOT FORMATION
Platelet Red Blood Cell

Fibrin

Fibrinolysis
Plasminogen

Extrinsic: t-PA, urokinase

Activation

Intrinsic: factor XIIa, HMWK, kallikrein

Exogenous: streptokinase

Fibrin, fibrinogen Plasmin Fibrin, fibrinogen degradation products

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FIBRINOLYSIS

Fibrinolysis

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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)

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HEMOSTASIS: ROLE OF FACTOR VII and TISSUE FACTOR

FVIIa Mechanism of Action

X TF VIIa Xa Va

II
IIa

TF-Bearing Cell
TF X VIIa Xa V Va

II
Va

Platelet
IIa

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

FACTOR VIIa Mechanism of Action

Increases the tissue factor (TF) occupancy In pharmacological doses binds to activated platelets Activates Factor X independent of tissue 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 AND CARDIOPULMONARY BYPASS

Contact Activation of Blood Proteins

Blood/Surface Interaction
Thrombin
Heparin

Plasmin

Kallikrein

Serine Protease Inhibitors

Clotting

Fibrinolysis

Kinins

Complement

Platelets

White Cells

Cytokines/Adhesion Molecules

Systemic Inflammatory Response

Contact Activation - The Role of Kallikrein

Negative Charged Surface
XII HK FXIIa PKK FXIIa

XII
HK XII HK FXI FXIIa XIa

PKK
Kallikrein FXIIa

Bradykinin

Kallikrein

Thrombin Generation

Factor XII
Factor XIIa Kinin Generation
Prekallikrein HMW-Kininogen Bradykinin Factor XII

Renin C1 Complement

Angiotensin Prorenin System System

Kallikrein
Factor XIIa

Factor XI

C1

_ Plasminogen

Coagulation Factor XIa System

Plasmin

Fibrinolytic System

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ANTICOAGULANTS/ ANTITHROMBINS

ANTITHROMBINS/ ANTICOAGULANTS
Argatroban Bivalirudin

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

LMWH
Anti-Xa

activity greater than AT activity, purified from UFH, MWt 4500-6000 Long duration of action, not reversible with protamine Included enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep)

Thrombin Inactivation: Heparin

Heparin/ATIII/IIa Ternary complex accelerates inactivation of IIa by ATIII IIa

IIa ATIII
Pentasaccharide sequence

ATIII

Pentasaccharide sequence

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

Factor Xa Inactivation: LMWH/Heparin

Pentasaccharide sequence

Xa

ATIII

ATIII

Xa

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

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

LMWHClinical Applications

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

hospitalization
In patients undergoing knee

replacement at risk of TE

In patients undergoing abdominal surgery who are

complications

Treatment of DVT/PE Ischemic complications of unstable angina and non-Q wave MI

Biological Consequences of Reduced Binding of LMWH to Proteins and Cells

Binding Target Thrombin Proteins Macrophages Platelets Osteoblasts Biological Effects Reduced anti-IIa to anti-Xa ratio More predictable anticoagulant response Cleared through renal mechanism Reduced incidence of heparin-dependent antibody Reduced activation of osteoclasts Clinical Consequences Unknown Monitoring of anticoagulant effect unnecessary Longer plasma half-life; once daily subcutaneous treatment effective Reduced incidence of heparin-induced thrombocytopenia Lower incidence of osteopenia

Dalen JE, Hirsh J. Fifth ACCP Consensus Conference on Antithrombotic Therapy. Chest 1998;114: 501s

Heparin/LMWHAdverse Effects
Heparin
Bleeding

LMWH
Bleeding Thrombocytopeni

Thrombocytopeni

a Osteoporosis Hypersensitivity

a Hypersensitivity

LMWHSpecial 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.
Adapted from the black box warning of LMWH

WarfarinMechanism of Action
Vitamin K VII

Vitamin K Utilization Reduced

Synthesis of IX Dysfunctional X Coagulation Factors II

Warfarin

WarfarinIndications
Prophylaxis and/or treatment
Venous

of:

thrombosis and its extension Pulmonary embolism

Thromboembolic complications Reduce risk

associated with AF and/or cardiac valve replacement of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MI

Elimination Half-Lives of Vitamin K-Dependent Proteins

Protein Factor VII Factor IX Factor II Factor X Protein C Protein S Half-Life 46 hours 24 hours 60 hours 4872 hours 8 hours 30 hours

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

WarfarinAdverse Effects
Fatal

or non-fatal hemorrhage from any tissue or organ Necrosis of skin and other tissues Other adverse reactions reported less frequently include:
Systemic
Alopecia Purple

cholesterol microembolization

toes syndrome, urticaria, dermatitis including bullous eruptions

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