CONTROL OF HEMOSTASIS

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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

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SIMPLIFIED CLINICIANS VIEW OF HEMOSTASIS

• Platelet/coagulation factor activation
• Lots of exciting biochemistry
• CLOT

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COMPONENTS OF HEMOSTASIS

• Vasculature
• Coagulation proteins
• Platelets

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Hemostasis
Subendothelial matrix
Hemostatic plug
Endothelial cell
WBC
WBC
Fibrin
RBC
Platelets
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COAGULATION PATHWAYS
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Coagulation Pathways
Intrinsic Pathway
Extrinsic Pathway
IX
Tissue Factor VII
TF Pathway
Contact
X
XI
TF-VIIa
PL
Common Pathway
XIIa
HKa
Prothrombin
XIa
PL
(Tenase)
IXa
PL
VIIIa
Xa
XIII
Va
(Prothrombinase)
Thrombin
Protein C, Protein S, Antithrombin III
XIIIa
Fibrinogen
Fibrin (strong)
Fibrin (weak)
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Normal Hemostasis Pivotal role of TF/VIIa
II
X
VIII/vWF
VIIa
TF
Xa
IIa
Va
VIIIa
TF-Bearing Cell
TF
V
Va
VIIa
IX
Platelet
II
IXa
X
IIa
Xa
VIIIa
IXa
Va
Activated Platelet
VIIa
IXa
Va
IIa
Xa
VIIIa
II
IX
X
Hoffman et al. Blood Coagul Fibrinolysis
19989(suppl 1)S61.
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PLATELET ACTIVATION PATHWAYS
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Platelet Activation Pathways (1)
COLLAGEN
THROMBIN

ADP
GpIIb/IIIa
Platelet
GpIb
Adrenaline
Adhesion
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Platelet Activation Pathways (2)
Thrombin
ADP
Platelet
Fibrinogen
Platelet Aggregation
Herbert. Exp Opin Invest Drugs 19943449-455.
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CLOT FORMATION
Platelet
Red Blood Cell
Fibrin
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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
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Fibrinolysis
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CONDITIONS PRODUCING COAGULOPATHY
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Conditions of coagulopathy

• Hemophilia
• Platelet disorders
• Liver disease
• DIC
• Dilution coagulopathy
• Anticoagulant treatment

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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
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FVIIa Mechanism of Action
II
X
TF
VIIa
Xa
IIa
Va
TF-Bearing Cell
TF
V
Va
Platelet
II
X
VIIa
Xa
IIa
Va
Activated Platelet
Hoffman et al. Blood Coagul Fibrinolysis
19989(suppl 1)S61.
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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 1S107-11, 2000.
• Proceedings of the National Academy of Sciences.
  96(16)8925-30, 1999.
• Haemostasis. 30 Suppl 241-7, 2000. Thrombosis
  Research. 98(4)311-21, 2000.

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CONTACT ACTIVATION AND CARDIOPULMONARY BYPASS
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Clotting
Fibrinolysis
Kinins
Complement
Platelets
White Cells
Cytokines/Adhesion Molecules
Systemic Inflammatory Response
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Contact Activation - The Role of Kallikrein
Negative Charged Surface
XII
HK
XII
FXIIa
PKK
HK
HK
XII
FXIIa
PKK
FXI
Kallikrein
FXIIa
FXIIa
Bradykinin
Kallikrein
XIa
Thrombin Generation
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Factor XII
Prekallikrein
Factor XIIa
HMW-Kininogen
Kinin Generation
Factor XII
Bradykinin
Factor XI
Prorenin
Angiotensin System
Kallikrein
Factor XIIa
Renin
Coagulation System
C1
Complement System
Factor XIa
Fibrinolytic System
Plasmin
Plasminogen
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ANTICOAGULANTS/ANTITHROMBINS
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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
  20011411043

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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)

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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
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Factor Xa Inactivation LMWH/Heparin
Pentasaccharide sequence
ATIII
Xa
Heparin/ATIII Ternary complex not necessary to
accelerate inactivation of Xa by ATIII
LMW Heparin/ATIII Ternary complex not necessary
to accelerate inactivation of Xa by ATIII
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LMWHClinical Applications

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

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Biological Consequences of Reduced Binding of
LMWH to Proteins and Cells
Binding Target Biological Effects Clinical
Consequences Thrombin Reduced anti-IIa
to Unknown anti-Xa ratio Proteins More
predictable Monitoring of anticoagulant anticoagu
lant response effect unnecessary Macrophages Clear
ed through renal Longer plasma half-life mechani
sm once daily subcutaneous treatment
effective Platelets Reduced incidence of Reduced
incidence of heparin-dependent heparin-induced a
ntibody thrombocytopenia Osteoblasts Reduced
activation of Lower incidence of osteoclasts oste
openia
Dalen JE, Hirsh J. Fifth ACCP Consensus
Conference onAntithrombotic Therapy. Chest
1998114 501s
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Heparin/LMWHAdverse Effects

• LMWH
• Bleeding
• Thrombocytopenia
• Hypersensitivity

• Heparin
• Bleeding
• Thrombocytopenia
• Osteoporosis
• Hypersensitivity

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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
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WarfarinMechanism of Action
Vitamin K
VII
Synthesis of Dysfunctional Coagulation Factors
IX
X
II
Warfarin
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WarfarinIndications

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

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Elimination Half-Lives of Vitamin K-Dependent
Proteins
Protein Half-Life Factor VII 46 hours Factor
IX 24 hours Factor II 60 hours Factor X 4872
hours Protein C 8 hours Protein S 30 hours
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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

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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 cholesterol microembolization
• Alopecia
• Purple toes syndrome, urticaria, dermatitis
  including bullous eruptions

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LOVEHEMOSTASIS

• Everybody talks about it, nobody understands it.
• JH Levy 2000