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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
Membrane Phospholipids
Arachidonic Acid
Phospholipase A2
PGG2; PGH2
Cyclooxygenase
TxA2
Thromboxanesynthase
Promote platelet aggregation and vasoconstriction
PlateletsProstacyclinsynthase
Adenylate cyclase
PGI2 released(+)
Inhibit platelet aggregation and vasoconstriction
(-)
EndothelialCells
Inhibiting Platelet Aggregation With Aspirin
• Aspirin is cyclooxygenase inhibitor• Inhibits platelet aggregation by
lowering thromboxane A2 levels
Structure And Cleavage Of Fibrinogen
• Fibrinogen molecule has 2,2,2 arrangement
• Thrombin cleavage of N-terminal peptides results in fibrin monomer
Cross-linking Of Fibrin Monomers
• Isopeptide bonds form between side chains at C-termini• Forms “hard clot”
(factor XIII)
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