Hemostasis & Thrombosis: Platelet Disorders Beth A. Bouchard

1. Hemostasis & Thrombosis: Platelet Disorders Beth A. Bouchard BIOC 212: Biochemistry of Human Disease Spring 2005

2. HEMOSTASIS Hemorrhage Thrombosis Hemostasis

3. HEMOSTASIS (CONT.) 1). INITIATION Vessel wall – endothelial cells and subendothelial components 2). LOCALIZATION Platelets – circulating cellular elements 3). PROPAGATION/AMPLIFICATION Plasma coagulation proteins (factors) 4). TERMINATION Plasma coagulation protein inhibitors 5). ELIMINATION Fibrinolytic system

4. Vessel Wall: Endothelial cells • Physically separate platelets from subendothelial proteins that can induce platelet activation • Produce 2 potent vasodilators and inhibitors of platelet function: prostacyclin (prostaglandin I2, PGI2) and nitric oxide Increase the concentration of the cyclic nucleotides cGMP and cAMP in platelets, which down regulate the signalling pathways that support platelet activation • Express CD39 on their surface, which enzymatically hydrolzes ADP, a potent platelet agonist release by activated platelets

6. Vessel Wall (cont.)

7. Response to Vessel Wall Injury: Platelet adhesion and activation • Exposure of flowing blood and platelets to subendothelial components • Platelets bind to the subendothelial collagen bound tovon Willebrand factor (vWF), which is secreted from endothelial cells directly into the subendothelial space or adsorbed from plasma following endothelial cell secretion • vWf also binds directly to platelets via glycoprotein Ib-IX • Platelet interactions with collagen (via a specific platelet membrane receptor) and platelet activating factor (PAF), from the vessel wall, leads to their activation

8. Platelets adhered to damaged endothelium

9. Response to Vessel Wall Injury: Vasoconstriction • Temporarily reduces local blood flow and hence, blood loss • Mediated in part by serotonin and thromboxane A2 (TXA2) from activated platelets Serotonin is released from platelet dense granules TXA2 is a product of platelet prostaglandin metabolism

10. PLATELETS

11. PLATELETS (CONT.) Platelet plug

12. Platelet Plug Formation = 1° hemostasis

13. Platelet Plug Formation: Platelet activation • Bind to subendothelial proteins and associated vWF subsequent to blood vessel injury • Activated via their interaction with collagen and PAF • Additional platelet agonists include ADP, epinephrine, thrombin, immune complexes, and high shear stress – all of the compounds interact with specific platelet membrane receptors • Several platelet activation pathways are initiated

14. Platelet Plug Formation: Platelet activation events • Platelet shape change: extend pseudopodia, which facilitates aggregation and coagulant activity • Release of alpha and dense granule contents including a number of compounds involved in hemostasis • Aggregation

15. Activated platelets

16. Platelet Plug Formation: Platelet aggregation • Platelet activation results in the functional expression of membrane receptors normally expressed in a non-functional state (glycoprotein IIb-IIIa) • Fibrinogen from the plasma or released from activated platelet alpha-granules binds to activated glycoprotein IIb-IIIa membrane receptors effectively bridging platelets to each other

17. Platelets adhered to and aggregated upon collagen

18. Platelet Plug Formation

19. Platelet Plug Formation • Measured clinically as the bleeding time • Normal bleeding time is from 2 – 10 min • Usually the bleeding time is sufficient to detect defects of platelet adhesion and aggregation, in which it is prolonged

20. Disorders of Platelet Adhesion or Aggregation • Affecting constituents of the vessel wall • Affecting the ability of the platelet to interact with the subendothelium at sites of blood vessel injury • Affecting the ability of the platelet to interact with other platelets

21. Vessel Wall Defects • von Willebrand’s disease: a group of autosomal dominant disorders that result in reduced or abnormal synthesis of vWF • Defects in collagen synthesis Ehlers-Danlos Syndrome: congenital defect in collagen synthesis Scurvy: results from vitamin C (ascorbic acid) deficiency, which is involved in collagen synthesis Excess exogenous or endogenous corticosteroids: also leads to acquired deficiency in collagen synthesis

22. Platelet Defects • Bernard-Soulier Syndrome: expression of low levels of or defective glycoprotein Ib-IX on the platelet surface • Glanzmann’s thrombasthenia: expression of low levels of or defective glycoprotein IIb-IIIa on the platelet surface

23. Other Defects • Fibrinogen: deficiency or production of abnormal protein • Acquired disorders include low platelet count (thrombocytopenia) as a result of defective formation of platelets by the bone marrow or excessive destruction of platelets

24. Antiplatelet Drugs