The Cell Based Model of Coagulation

1
The Cell Based Model of Coagulation

• A pharmacological perspective

2
Topics

• Physiology
• Cascade Model
• Cell Based Model
• Pharmacology
• Anti-platelet Drugs
• Anti-factor Drugs
• Anti-cross linking Drugs
• Anti-fibrinolytic drugs

3
Part One

• Physiology

4
Hemostasis

• Vasoconstriction
• Platelet plug formation
• Activation
• Adherence
• Aggregation
• Stabilization of platelet plug
• Coagulation cascade
• Fibrin

5
Cascade Model
XII
XIIa
VII
XI
TF
XIa
IX
X
X
IIa
II
Fibrin
Fibrinogen
6
Intrinsic
XII
XIIa
Extrinsic
VII
XI
TF
XIa
IX
X
X
IIa
II
Common
Fibrin
Fibrinogen
7
Tests
XII
XIIa
VII
XI
TF
XIa
IX
X
X
IIa
II
Fibrin
Fibrinogen
8
Problems
XII
XIIa
?Ca2
VII
XI
TF
C
XIa
B
IX
A
X
X
?Ca2
IIa
II
?Ca2
Fibrin
Fibrinogen
9
Cell Based Theory

• Platelets and IIa are central
• Sequence
• Initiation
• Amplification
• Propagation

10
XII
XIIa
VII
XI
TF
XIa
IX
X
X
IIa
II
Fibrin
Fibrinogen
11
Xa
IIa
XIa
XIa
IXa
VIIIa
Xa
Va
IIa
Fibrin
Fibrinogen
Fibrin
Fibrinogen
12
Tissue factor bearing cell
Initiation
Xa
IIa
Amplification
IIa
Plt
Plt
Plt
Propagation
Xa
Plt
Fg
Fb
IIa
Fb
Fb
Plt
Plt
Fb
Fb
vWF
Subendothelial collagen
vWF
13
Platelet activation

• Triggered by
• Sub-endothelial collagen
• IIa
• ADP
• TXA2
• 5HT
• Epinephrine

14
Platelet activation

• Results in
• Greatly increased surface area
• Dense granules release Ca2, 5HT, TXA2, ADP
• Alpha granules release factor V, fibrin, VWF

15
Platelet activation

• Platelet phospholipid bilayer is actively
  controlled
• Resting internal surface is procoagulant
• Bilayer everts during activation, exposing
  procoagulant surface

16
Tissue factor bearing cell
Xa
IIa
Plt
IIa
IIa
Plt
IIa
VIIIa
Plt
Plt
IIa
Va
XIa
vWF
Plt
IIa
IXa
Fg
Plt
Plt
Propagation
Xa
Plt
Fg
Fb
IIa
Fb
Fb
Plt
Plt
Fb
Fb
vWF
Subendothelial collagen
vWF
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Part Two

• Pharmacology

18
Part Two - Pharmacology

• Topics
• Anti-platelet Drugs
• Anti-factor Drugs
• Anti-cross linking Drugs
• Anti-fibrinolytic Drugs

19
Aspirin

• Salicylate that irreversibly acetylates COX
  enzymes
• Prevents thromboxane generation
• Thromboxane is a potent stimulator of platelet
  activation and aggregation

20
Tissue factor bearing cell
Xa
IIa
Plt
IIa
IIa
Plt
IIa
VIIIa
Plt
Plt
IIa
Va
XIa
vWF
Plt
IIa
IXa
Fg
Plt
Plt
Xa
Plt
Fg
Fb
IIa
Fb
Fb
Plt
Plt
Fb
Fb
vWF
Subendothelial collagen
vWF
21
Clopidogrel

• Irreversibly inactivate platelet ADP receptors
• Thus preventing activation

22
Tissue factor bearing cell
Xa
IIa
Plt
IIa
IIa
Plt
IIa
VIIIa
Plt
Plt
IIa
Va
XIa
vWF
Plt
IIa
IXa
Fg
Plt
Plt
Xa
Plt
Fg
Fb
IIa
Fb
Fb
Plt
Plt
Fb
Fb
vWF
Subendothelial collagen
vWF
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Heparin

• Sulfated glycosaminoglycan naturally bound to
  endothelial cells
• Negatively charged highly bound in plasma
• Cleared by reticuloendothelial system

24
Heparin

• Binds to AT III, and increases its activity 1000
  fold
• Heparin-ATIII binds to IIa, IXa, Xa, XIa and
  inactivates them

25
Tissue factor bearing cell
Xa
IIa
Plt
IIa
IIa
Plt
IIa
ADP
VIIIa
Plt
Plt
IIa
Va
XIa
vWF
Plt
IIa
IXa
Fg
Plt
Plt
Xa
Plt
Fg
Fb
IIa
Fb
Fb
Plt
Plt
Fb
Fb
vWF
Subendothelial collagen
vWF
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Heparin

• Binds to Anti Thrombin III, and increases its
  activity 1000 fold
• Heparin-ATIII binds to IIa, IXa, Xa, XIa and
  inactivates them
• Requires AT III for its actions

27
Heparin

• Problems
• Thrombocytopenia
• HITTS
• IgG mediated
• 4-14 days to develop
• Thrombosis

28
LMWH

• Derived from heparin by chemical depolymerization
• XaIIa activity 41

29
Tissue factor bearing cell
Xa
IIa
Plt
IIa
IIa
Plt
IIa
VIIIa
Plt
Plt
IIa
Va
XIa
vWF
Plt
IIa
IXa
Fg
Plt
Plt
Xa
Plt
Fg
Fb
IIa
Fb
Fb
Plt
Plt
Fb
Fb
vWF
Subendothelial collagen
vWF
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LMWH

• Advantages over heparin
• Markedly reduced protein binding
• Lower incidence of HITTS
• Renal clearance
• More effective thromboprophylaxis

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Fondaparinux

• Synthetic anticoagulant
• Does not cause HITTS
• Inhibits Xa
• Renally excreted

32
Warfarin

• Coumarin derivative with high oral
  bioavailability
• Interferes with vitamin K regeneration

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Vitamin K dependent factors

• Factors II, VIII, IX X
• Carboxylation allows interaction with platelet
  membrane
• Interaction requires Ca2

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Tissue factor bearing cell
Xa
IIa
Plt
IIa
IIa
Plt
IIa
VIIIa
Plt
Plt
IIa
Va
XIa
vWF
Plt
IIa
IXa
Fg
Plt
Plt
Xa
Plt
Fg
Fb
IIa
Fb
Fb
Plt
Plt
Fb
Fb
vWF
Subendothelial collagen
vWF
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Warfarin

• High protein binding
• Hepatic clearance via inducable enzymes

36
Warfarin

• Levels increased by
• Protease inhibitors
• Macrolide antibiotics
• Chloramphenicol
• Azole antifungals
• Bergamottin (constituent of grapefruit juice)
• Verapamil
• Amiodarone

• Ciprofloxacin
• Cyclosporin
• Diltiazem
• Ergotamine
• Metronidazole
• Norfloxacin
• SSRIs
• Fluoxetine/norfluoxetine
• Fluvoxamine
• Cimetidine
• Buprenorphine

37
Lepirudin

• Recombinant hirudin
• Directly binds to thrombin
• Monitored by aPTT

38
Tissue factor bearing cell
Xa
IIa
Plt
IIa
IIa
Plt
IIa
VIIIa
Plt
Plt
IIa
Va
XIa
vWF
Plt
IIa
IXa
Fg
Plt
Plt
Xa
Plt
Fg
Fb
IIa
Fb
Fb
Plt
Plt
Fb
Fb
vWF
Subendothelial collagen
vWF
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Lepirudin

• Renally excreted
• No effective antidote
• Half-life 2 hours

40
Abciximab

• Monoclonal antibody
• High affinity for platelet IIa/IIIb receptor for
  fibrin
• Plasma half life 20 minutes
• Has activity for 2 days

41
Tissue factor bearing cell
Xa
IIa
Plt
IIa
IIa
Plt
IIa
VIIIa
Plt
Plt
IIa
Va
XIa
vWF
Plt
IIa
IXa
Fg
Plt
Plt
Xa
Plt
Fg
Fb
IIa
Fb
Fb
Plt
Plt
Fb
Fb
vWF
Subendothelial collagen
vWF
42
Tranexamic Acid

• Competitive inhibitor of the activation of
  plasminogen
• Renally excreted, half-life 2 hours
• Provides survival benefit in trauma patients with
  hemodynamic instability

43
Tissue factor bearing cell
Xa
IIa
Plt
IIa
IIa
Plt
IIa
VIIIa
Plt
Plt
IIa
Va
XIa
vWF
Plt
IIa
IXa
Fg
Plt
Plt
Xa
Plt
Fg
Fb
IIa
Fb
Fb
Plt
Plt
Fb
Fb
vWF
Subendothelial collagen
vWF
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Questions?