Anti-Coagulants

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
• Structure, properties, biochemical mechanism

2
The Clotting Process
Taken from Desai UR (2004) Med. Res. Rev. 24,
151-181.
3
Chemical Process of Clotting
4
Heparin and Low molecular weight heparins
Structure and sequence
5
Pentasaccharide
6
Biochemical Mechanism of Heparin Action
7
Heparin can induce clots!!
8
Problems with Heparin therapy
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

9
Coumarins and 1,3-indanediones
10
Clinically useful coumarins and 1,3-indanediones
11
Biochemical Mechanism of Action