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Coagulation and Anti-coagulation

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

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Coagulation and Anti-coagulation

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  1. 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 MEDC 604 Anti-coagulants

  2. Scanning Electron Micrograph of a Clot MEDC 604 Anti-coagulants

  3. Physical Process of Clotting MEDC 604 Anti-coagulants

  4. 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 XIII IIa Fibrinogen Xa IIa IIa VIIa TF XIIIa X Fibrin CLOT monomers VII Desai, U. R., VCU (2005) MEDC 604 Anti-coagulants

  5. Important Characteristics of Clotting Cascade • Activation of Enzymes • Amplification • Clot Localization MEDC 604 Anti-coagulants

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

  7. C C E1 E1 A B E2 A E2 F F X E3 E4 D Y D E4 E3 G G Important Characteristics of Clotting Cascade • Amplification MEDC 604 Anti-coagulants

  8. 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 MEDC 604 Anti-coagulants

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

  10. Pentasaccharide MEDC 604 Anti-coagulants

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

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

  13. Designing Heparin Mimics • Binding in the Pentasaccharide Binding Site • Binding in the Extended Heparin Binding Site MEDC 604 Anti-coagulants

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