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Hemostasis

Hemostasis. Constriction of vessel Aggregation of platelets Clotting: web of fibrin polymers. Platelet Activation. Exposed extracellular matrix at injury binds receptors on platelets Granule release activates additional platelets. Aggregation Of Platelets.

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Hemostasis

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  1. Hemostasis • Constriction of vessel • Aggregation of platelets • Clotting: web of fibrin polymers

  2. Platelet Activation • Exposed extracellular matrix at injury binds receptors on platelets • Granule release activates additional platelets

  3. Aggregation Of Platelets • Activated platelets adhere strongly to ECM and to each other • Von Willebrandt factor associates platelets with ECM • Fibrinogen cross-links platelets using GPIIb/IIIa receptors • GPIIb/IIIa inhibitors as drugs

  4. Signaling Using Prostaglandins And Thromboxanes • Cyclooxygenase converts arachidonic acid to PGG2 • PGG2 converted to: • Thromboxane A2 (platelets); promotes platelet aggregation • PGI2 (endothelial cells); inhibits platelet aggregation

  5. Membrane Phospholipids Phospholipase A2 Arachidonic Acid Cyclooxygenase Endothelial Cells Platelets PGG2; PGH2 Thromboxane synthase Prostacyclin synthase PGI2 released TxA2 (-) (+) Promote platelet aggregation and vasoconstriction Adenylate cyclase Inhibit platelet aggregation and vasoconstriction

  6. Inhibiting Platelet Aggregation With Aspirin • Aspirin is cyclooxygenase inhibitor • Inhibits platelet aggregation by lowering thromboxane A2 levels

  7. Formation Of Fibrin Network • Conversion of soluble fibrinogen to insoluble fibrin fibers

  8. Structure And Cleavage Of Fibrinogen • Fibrinogen molecule has a2,b2,g2 arrangement • Thrombin cleavage of N-terminal peptides results in fibrin monomer

  9. Formation Of Fibrin Fibers • Monomers associate as half-staggered arrays • Forms “soft clot”

  10. Cross-linking Of Fibrin Monomers (factor XIII) • Isopeptide bonds form between side chains at C-termini • Forms “hard clot”

  11. Pathways For Stimulating Fibrinogen Cleavage • Cascade of proteases that are activated by cleavage • Two pathways activated by different stimuli feed into common pathway

  12. Intrinsic Pathway • Everything needed for pathway contained in blood • Stimulated by contact with negatively charged surface

  13. Extrinsic Pathway • Stimulated by tissue factor (thromboplastin) that is normally buried below endothelium

  14. Common Pathway • Activated factor X cleaves cleaves prothrombin into thrombin • Thrombin cleaves fibrinogen

  15. Structure And Cleavage Of Prothrombin • Two factor X cleavage sites • Thrombin composed of peptides A and B • N terminal region released

  16. Role Of Vitamin K In Clotting • Carboxylation of glutamic acid into Gla required for some clotting factors • Vitamin K is cofactor for modifying enzyme • Dicoumarol and warfarin inhibit clotting through vitamin K cycle

  17. Function Of Gla Residues In Prothrombin Cleavage • Cleavage requires association with phospholipid membrane through Ca2+ bridges • Gla strongly attracts Ca2+

  18. Blood Clotting Disorders • Hemophilia A: inherited deficiency of factor VIII • Von Willebrandt disease: inherited deficiency of vWf

  19. Controlling Blood Clotting • Proteolysis of Factors V and VIII by activated protein c-protein s complex • Inherited disorders protein c, protein s, Factor V

  20. Controlling Blood Clotting Heparin • Heparin increases activity of antithrombin Blood clotting proteases Antithrombin Plasminogen activator • Plasminogen activator protease produces active plasmin Plasminogen Plasmin Fibrin clot Peptides

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