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Anti-Coagulants

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

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Anti-Coagulants

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  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 MEDC 604 Anti-coagulants

  2. A) Physical Process B) Chemical Process Wound Wound aspirin antithrombins platelet activation factor Xa fibrinogen release thrombin release of of ADP generation thromboxane A2 thrombin prothrombin fibrin (monomers) vitamin K-dependent g-carboxylation of Glu residues Further activation of platelets ADP receptor antagonists GP IIb-IIIa receptor antagonists fibrin (polymer) Platelet aggregation coumarins CLOT The Clotting Process Taken from Desai UR (2004) Med. Res. Rev. 24, 151-181. MEDC 604 Anti-coagulants

  3. Chemical Process of Clotting MEDC 604 Anti-coagulants

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

  5. Pentasaccharide MEDC 604 Anti-coagulants

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

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

  8. AT M AT AT AT Adapted from Hirsh et al. (2001) Chest 119, 64S-94S 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 MEDC 604 Anti-coagulants

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

  10. Clinically useful coumarins and 1,3-indanediones MEDC 604 Anti-coagulants

  11. Biochemical Mechanism of Action MEDC 604 Anti-coagulants

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