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 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

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

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

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

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

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

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

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

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

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

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

Common Pathway Activated factor X cleaves cleaves prothrombin into thrombin Thrombin cleaves fibrinogen

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

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

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

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

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

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