1. Anti-Coagulants Physical Process of Clotting
Chemical Process of Clotting
Fibrin formation, extrinsic and intrinsic pathways
Anti-coagulants
Definition
Heparin, Low molecular weight heparins, pentasaccharide
Structure, properties, biochemical mechanism
Direct Thrombin Inhibitors
Coumarins and 1,3-indanediones
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MEDC 604 Anti-coagulants

2. A) Physical Process B) Chemical Process
The Clotting Process
A) Physical Process B) Chemical Process
Wound
antithrombins
factor Xa
thrombin prothrombin
fibrinogen
fibrin
(monomers)
(polymer)
vitamin K-dependent
g-carboxylation of
Glu residues
coumarins
platelet activation
release thrombin release of
of ADP generation thromboxane A2
Further activation of platelets
Platelet aggregation
aspirin
ADP
receptor
antagonists
GP IIb-IIIa
CLOT
Taken from Desai UR (2004) Med. Res. Rev. 24,
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MEDC 604 Anti-coagulants

3. Chemical Process of Clotting
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MEDC 604 Anti-coagulants

4. Heparin and Low molecular weight heparins
Structure and sequence
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MEDC 604 Anti-coagulants

5. Pentasaccharide
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MEDC 604 Anti-coagulants

6. Biochemical Mechanism of Heparin Action
AT + H
AT:H
AT-E H E
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MEDC 604 Anti-coagulants

7. Heparin can induce clots!!
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MEDC 604 Anti-coagulants

8. Problems with Heparin therapyAT
Adapted from Hirsh et al. (2001) Chest 119, 64S-94S
proteins H EC
Heparin-induced thrombocytopenia …. 3.5% of treated patients
Heparin resistance …. 25% of VTE patients
Unable to inhibit factor Xa in prothrombinase complex
Unable to inhibit thrombin bound to fibrin
Binds to von Willebrand factor …. Inhibition of platelet function
Binds to platelets …. inhibit platelet aggregation
Binds to endothelial cells …. Heparin-induced bleeding
Inhibits proliferation of vascular SMC
Activates osteoclasts to promote bone loss
Causes release of TFPI …. Added anticoagulant activity
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MEDC 604 Anti-coagulants

9. Coumarins and 1,3-indanediones
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MEDC 604 Anti-coagulants

10. Clinically useful coumarins and 1,3-indanediones
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11. Biochemical Mechanism of Action
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MEDC 604 Anti-coagulants