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 I 2, PGI 2 ) 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 to von 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 A 2 (TXA 2 ) from activated platelets Serotonin is released from platelet dense granules TXA 2 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. 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