Physiology of blood platelet activation.
Blood platelets interact with a variety of soluble agonists such as epinephrine and adenosine diphosphate (ADP); many insoluble cell matrix components, including collagen and laminin, and biomaterials used for construction of invasive medical devices. These interactions stimulate specific receptors and glycoprotein-rich domains (integrins and nonintegrin) on the plasma membrane and lead to the activation of intracellular effector enzymes. The majority of regulatory events appear to require free calcium. Ionized calcium is the primary bioregulator, and a variety of biochemical mechanisms modulate the level and availability of free cytosolic calcium. Major enzymes that regulate the free calcium levels via second messengers include phospholipase C, phospholipase A2, and phospholipase D, together with adenylyl and guanylyl cyclases. Activation of phospholipase C results in the hydrolysis of phosphatidyl inositol 4,5-bisphosphate and formation of second messengers 1,2-diacylglycerol and inositol 1,4,5-trisphosphate (IP3). Diglyceride induces activation of protein kinase C, whereas IP3 mobilizes calcium from internal membrane stores. Elevation of cytosolic calcium stimulates phospholipase A2 and liberates arachidonic acid. Free arachidonic acid is transformed to a novel metabolite, thromboxane A2, by fatty acid synthetases. Thromboxane A2 is the major metabolite of this pathway and plays a critical role in platelet recruitment, granule mobilization and secretion. Up-regulation in signalling pathways will increase the risk for clinical complications associated with thromboembolic episodes. Down-regulation of signal transduction mechanisms may precipitate bleeding diathesis or stroke.
Rao
G H
GH
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis 55455.
D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D010716:Phosphatidylinositols / Q000378:metabolism; D010740:Phospholipases / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010974:Platelet Aggregation; D015290:Second Messenger Systems; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D010716:Phosphatidylinositols; D010740:Phospholipases; D002118:Calcium