HEMOSTASIS

1. HEMOSTASIS Primary hemostasis

2. HEMOSTASIS • Hemostasis • The process by which the body stops bleeding upon injury and maintains blood in the fluid state in the vascular compartment • Process is rapid and localized

3. HEMOSTASIS • The primary players in hemostasis include • Blood vessels • Platlets • Plasma proteins • Coagulation proteins – involved in clot formation • Fibrinolysis – involved in clot dissolution • Serine protease inhibitors • Other minor players include • Kinin system • Complement system

4. HEMOSTASIS • Defects • In blood vessels, platlets or serum proteins can be corrected by utilization of the other 2 players • In 2 of the 3 players results in pathologic bleeding Blood Vessels Plasma Proteins Platlets

5. HEMOSTASIS • Hemostasis can be divided into two stages • Primary hemostasis • Response to vascular injury • Formation of the “platelet plug” adhering to the endothelial wall • Limits bleeding immediately • Secondary Hemostasis • Results in formation of a stable clot • Involves the enzymatic activation of coagulation proteins that function to produce fibrin as a reinforcement of the platelet plug • Gradually the stable plug will be dissolved by fibrinolysis

6. FORMATION OF A STABLE PLUG

7. VASCULAR SYSTEM • Smooth and continuous endothelial lining is designed to facilitate blood flow • Intact endothelial cells inhibit platelet adherence and blood coagulation • Injury to endothelial cells promotes localized clot formation • Vasoconstriction • Narrows the lumen of the vessel to minimize the loss of blood • Brings the hemostatic components of the blood (platelets and plasma proteins) into closer proximity to the vessel wall • Enhances contact activation of platlets • Von Willebrand factor • Collagen fibers • Platlet membrane glycoprotein Ib • Activated platlets enhance activation of coagulation proteins

8. PRIMARY HEMOSTASIS • Platelets • Interact with injured vessel wall • Interact with each other • Produce the primary hemostatic plug • Primary platelet plug • Fragile • Can easily be dislodged from the vessel wall

9. PLATELETS • Platelets • Small, anucleated cytoplasmic fragments • Released from megakaryocytes in the BM • Megakaryocyte proliferation is stimulated by thrombopoietin (TPO) • Humoral factor • Produced primarily by liver, kidney, spleen, BM • Produced at a relatively constant rate • Normal platlet count is 150-400 x 109/L • Survive 9-12 days • Nonviable or aged platelets removed by spleen & liver • 2/3 of platelets circulate in the peripheral blood • 1/3 are sequestered in the spleen • These 2 pools are in equilibrium and constantly exchanging • Spontaneous hemorrhaging occurs when platlet count gets below 10 x 109/L

10. PLATLETS

11. MATURE MAGAKARYOCYTE

12. PLATLET RELEASE

13. PLATLET FUNCTION • Platlets function to • Provide negatively charged surface for factor X and prothrombin activation • Release substances that mediate vasoconstriction, platlet aggregation, coagulation, and vascular repair • Provide surface membrane proteins to attach to other platlets, bind collagen, and subendothelium

14. PLATELETS • Are the primary defense against bleeding • Circulate in resting state • Have minimal interaction with other blood components or the vessel wall • Morphology of resting platelet is smooth, discoid • When stimulated by endothelial damage, platlets become activated and they • Become round and ‘sticky’ • Build a hemostatic plug • Provide reaction surface for proteins that make fibrin • Aid in wound healing • Platlet activation and plug formation involves • Adhesion • Shape change • Secretion • Aggregation

15. ADHESION • Damage to endothelium exposes blood to the subepithelial tissue matrix with adhesive molecules • Platlet receptor GPIb binds to subendothelium collagen fibers through von Willebrand’s factor (vWF) • Platlet adherence stops the initial bleeding

16. SHAPE CHANGE • Following vessel injury and platlet exposure to external stimuli, platlets change shape from circulating discs to spheres with pseudopods • Shape change is mediated by an increase in cytosolic calcium • Exposure of platlet membrane phospholipids promotes the assembly of vitamin-K dependent factors on the platlet membrane surface • Activated platlets adhere to exposed collagen

17. CHANGE IN PLATLET SHAPE

18. AGGREGATION • Platlet-to-platlet interaction • Begins 10-20 seconds after vascular injury and platlet adhesion • Requires dense granule release from the adhering platlets • Requires Ca++and ATP • Requires fibrinogen and fibrinogen receptors GPIIb and IIIa • Mechanism: • ADP released from platlet cytoplasm upon adherence induces exposure of fibrinogen receptors GPIIb and IIIa • Fibrinogen binds to the exposed GPIIb and IIIa • Extracellular Ca++-dependent fibrinogen bridges form between adjacent platlets, thereby promoting platlet aggregation • This is primary or reversible aggregation • Secondary aggregation begins with the release of dense granules • Secondary aggregation is considered irreversible

19. SECRETION • Secondary aggregation begins with platlet secretion of dense granules • Dense granules contain large amounts of ADP • ADP binds to the platlet membrane triggering the synthesis and release of TXA2 • The release of large amounts of ADP combined with TXA2 amplifies the initial aggregation of platlets into a large platlet mass

20. FORMATION OF PRIMARY HEMOSTATIC PLUG

21. PLATELETS AND SECONDARY HEMOSTASIS • Primary platelet plug is • Unstable and easily dislodged • Secondary hemostasis • Fibrin formation stabilizes the platelet plug • Proteins interact to form fibrin assemble on negatively charged membrane phospholipids of activated platelets