Activation of platelets, e.g., upon contact with collagen of the extracellular matrix after injury to the vascular wall, constitutes the immediate and decisive step in initiating the process of primary hemostasis, i.e., cessation of bleeding. However, in the absence of vascular injury, platelets can be activated as a result of damage to the endothelial cell lining of blood vessels. Among the multiple functions of the endothelium, the production of NO' and prostacyclin plays an important role. Both substances inhibit the tendency of platelets to adhere to the endothelial surface (platelet adhesiveness). Impairment of endothelial function, e.g., due to chronic hypertension, cigarette smoking, chronic elevation of plasma LDL levels or of blood glucose, increases the probability of contact between platelets and endothe-lium. The adhesion process involves GPIB/IX, a glycoprotein present in the platelet cell membrane and von Wille-brandfs factor, an endothelial membrane protein. Upon endothelial contact, the platelet is activated with a resultant change in shape and affinity to fibrinogen. Platelets are linked to each other via fibrinogen bridges: they undergo aggregation.
Platelet aggregation increases like an avalanche because, once activated, platelets can activate other platelets. On the injured endothelial cell, a platelet thrombus is formed, which obstructs blood flow. Ultimately, the vascular lumen is occluded by the thrombus as the latter is solidified by a vasoconstriction produced by the release of serotonin and thromboxane A2 from the aggregated platelets. When these events occur in a larger coronary artery, the consequence is a myocardial infarction; involvement of a cerebral artery leads to stroke.
The von Willebrandt's factor plays a key role in thrombogenesis. Lack of this factor causes thrombasthenia, a pathologically decreased platelet aggregation. Relative deficiency of the von WilleLullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
brandt's factor can be temporarily overcome by the vasopressin anlogue desmopressin (p. 164), which increases the release of available factor from storage sites.
Formation, Activation, and Aggregation of Platelets (B)
Platelets originate by budding off from multinucleate precursor cells, the me-gakaryocytes. As the smallest formed element of blood (dia. 1-4 jm), they can be activated by various stimuli. Activation entails an alteration in shape and secretion of a series of highly active substances, including serotonin, platelet activating factor (PAF), ADP, and thromboxane A2. In turn, all of these can activate other platelets, which explains the explosive nature of the process.
The primary consequence of activation is a conformational change of an in-tegrin present in the platelet membrane, namely, GPIIB/IIIA. In its active conformation, GPIIB/IIIA shows high affinity for fibrinogen; each platelet contains up to 50,000 copies. The high plasma concentration of fibrinogen and the high density of integrins in the platelet membrane permit rapid cross-linking of platelets and formation of a platelet plug.
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