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 11/9/2018 MEDC 604 Anti-coagulants

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, 151-181. 11/9/2018 MEDC 604 Anti-coagulants

Chemical Process of Clotting 11/9/2018 MEDC 604 Anti-coagulants

Heparin and Low molecular weight heparins Structure and sequence 11/9/2018 MEDC 604 Anti-coagulants

Pentasaccharide 11/9/2018 MEDC 604 Anti-coagulants

Biochemical Mechanism of Heparin Action AT + H AT:H AT-E + H E 11/9/2018 MEDC 604 Anti-coagulants

Heparin can induce clots!! 11/9/2018 MEDC 604 Anti-coagulants

Problems with Heparin therapy AT 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 11/9/2018 MEDC 604 Anti-coagulants

Coumarins and 1,3-indanediones 11/9/2018 MEDC 604 Anti-coagulants

Clinically useful coumarins and 1,3-indanediones 11/9/2018 MEDC 604 Anti-coagulants

Biochemical Mechanism of Action 11/9/2018 MEDC 604 Anti-coagulants