| Blood platelets form the initial hemostatic plug in small vessels, and the initial thrombus in arteries and veins.
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| PLATELET ACTIVATION EXPOSES GLYCOPROTEIN RECEPTORS |
| Platelet membrane receptors and their ligands, vWF and fibrinogen |
| Platelets have a key role in hemostasis and thrombosis, through adhesion to the vessel wall and subsequent aggregation to form a platelet-rich hemostatic plug or thrombus. These processes involve exposure of specific membrane glycoprotein receptors after platelet activation by several compounds (see Fig. 6.3). |
| Platelet receptor GPIb-IX plays a key part in the adhesion of platelets to subendothelium. It binds vWF, which also interacts with specific subendothelial receptors, including those on subendothelial collagen. Congenital deficiencies of GPIb-IX (Bernard-Soulier syndrome) or, more commonly, of vWF, result in a bleeding tendency. In contrast, high plasma concentrations of vWF are associated with increased risk of thrombosis. For patients at high risk of thrombosis, therapeutic strategies directed against vWF (for example anti-vWF antibodies) are currently being developed, to reduce the thrombotic risk. |
| Another receptor, GPIIb-IIIa has a key role in platelet aggregation. After platelet activation, hundreds of thousands of GPIIb-IIIa receptors can be exposed in a single platelet. These receptors interact with fibrinogen or vWF, which bind platelets together, forming a hemostatic or thrombotic plug. Congenital deficiency of GPIIb-IIIa (the rare Glanzmann's thrombasthenia) causes a severe bleeding disorder; in contrast, deficiencies of either fibrinogen or vWF cause a milder bleeding disorder, because these two ligands can substitute for each other. High plasma concentrations of fibrinogen are associated with increased risk of thrombosis, partly because of its platelet-binding activity. For patients at high risk of thrombosis, inhibitors of the GPIIb-IIIa receptor (such as antireceptor antibodies) are being developed and are proving to be clinically effective. |
| Platelets are circulating, anuclear microcells of mean diameter 2-3 mm. They are fragments of bone marrow
megakaryocytes, and circulate for about 10 days in the blood. The concentration of platelets in normal blood is 150-400 × 109/L (150-400 × 103/mm3).
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Platelets can be activated by several chemical agents, including adenosine diphosphate (ADP, released by platelets, erythrocytes, and endothelial cells), epinephrine, collagen, thrombin, and PAF; by immune complexes (generated during infections); and by high physical shear stresses (shear stress is the tangential force applied to the cells by the flow of blood). Most of the chemical agents appear to act by binding to specific receptors on the platelet surface membrane (see Fig. 6.3). After receptor stimulation, several pathways of platelet activation can be initiated, resulting in several phenomena:
- change in platelet shape from a disc to a sphere with extended pseudopodia - which facilitates aggregation and coagulant activity;
- release of several compounds involved in hemostasis from intracellular granules - for example ADP, serotonin, TXA2, and vWF;
- aggregation, via exposure of GPIb-IX membrane receptor and linking by vWF (under high shear conditions), and via exposure of another membrane glycoprotein receptor, GPIIa-IIIb and linking by fibrinogen (under low shear conditions);
- adhesion to the vessel wall via exposure of the GPIb-IX membrane receptor, through which vWF binds platelets to subendothelial collagen.
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| Finally, stimulation of the platelet membrane receptor triggers the activation of platelet membrane phospholipases, which hydrolyze membrane phospholipids, releasing arachidonic acid. Arachidonic acid is metabolized by cyclo-oxygenase and thromboxane synthase to TXA2, a potent but labile (half-life 30 seconds) mediator of platelet activation and vasoconstriction.
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