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. 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

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

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

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

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

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

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

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

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

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

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

17. 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

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

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

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

21. 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