Coagulation and Anti-coagulation Physical Process of Clotting Chemical Process of Clotting Fibrin formation, Extrinsic and Intrinsic pathways, Amplification, Activation of Enzymes, Clot Localization Inhibitors of Clotting Anti-platelets, anti-coagulants Antithrombin Heparin, Low molecular weight heparins, Heparin Pentasaccharide Structure, properties, biochemical mechanism Heparin mimics 10/12/2018 MEDC 604 Anti-coagulants

Scanning Electron Micrograph of a Clot 10/12/2018 MEDC 604 Anti-coagulants

Physical Process of Clotting 10/12/2018 MEDC 604 Anti-coagulants

The Chemical Process of Clotting HMWK XI XII XIIa IX Note: IXa and VIIIa work together to convert X into Xa. Xa and Va work together to convert II into IIa. IIa works on a number of steps. HMWK and TF are initiation points CLOT is the end point XIa X IXa VIII VIIIa IIa II Xa V Va IIa Fibrinogen XIII Xa IIa VIIa IIa TF X XIIIa Fibrin CLOT monomers VII Desai, U. R., VCU (2005) 10/12/2018 MEDC 604 Anti-coagulants

Important Characteristics of Clotting Cascade Activation of Enzymes Amplification Clot Localization 10/12/2018 MEDC 604 Anti-coagulants

Important Characteristics of Clotting Cascade Activation of Enzymes fXa (Arg323-Ile324) Ser562 fXa, Va PL, Ca2+ 1 fXa (Arg274-Thr275) Prothrombin Thrombin 10/12/2018 MEDC 604 Anti-coagulants

Important Characteristics of Clotting Cascade Amplification A E2 E1 C E3 D E4 F G A B X Y E2 10/12/2018 MEDC 604 Anti-coagulants

Regulation of Clotting Natural Anticoagulants Antithrombin, Tissue Factor Pathway Inhibitor, Protein C Natural Products as Anticoagulant Drugs Heparin-based anticoagulants Coumarin-based anticoagulants Tick anticoagulant peptide 10/12/2018 MEDC 604 Anti-coagulants

Heparin and Low molecular weight heparins Structure and sequence 10/12/2018 MEDC 604 Anti-coagulants

Pentasaccharide 10/12/2018 MEDC 604 Anti-coagulants

Structure of Antithrombin – Pentasaccharide Complex helix D helix P RCL helix A A) B) Lys136 Arg133 Lys132 Arg129 Lys125 Arg47 Arg46 Lys114 D E F G H EHBS PBS 10/12/2018 MEDC 604 Anti-coagulants

Biochemical Mechanism of Heparin Action AT + H AT:H AT-E + H E 10/12/2018 MEDC 604 Anti-coagulants

Designing Heparin Mimics Binding in the Pentasaccharide Binding Site Binding in the Extended Heparin Binding Site 10/12/2018 MEDC 604 Anti-coagulants