Shedding of adhesion receptors from the surface of activated platelets

When platelets are activated, several receptors are removed from the platelet surface. Cytoskeletal reorganizations can cause receptors to redistribute to intracellular membranes. In addition, receptors can be removed from the platelet surface by shedding of the receptor from the cell. Shedding can occur by at least two mechanisms. First, glycoprotein (GP)Ib alpha and GP V are shed from the membrane as a result of the proteolytic cleavage of the extracellular domain of these receptors from the platelet. The protease responsible for this cleavage appears to be a membrane-bound divalent cation-dependent protease other than calpain. Proteolytic cleavage does not occur until secretion is well under way and occurs whether platelets aggregate or not. Soluble forms of both GP Ib alpha and GP V are present in the plasma, where they may serve as feedback inhibitors limiting the development of thrombi. Future studies will be needed to identify the protease(s) responsible for removing the membrane receptors and to determine whether cleavage of the receptors from activated platelets results from activation of the protease(s), exposure of the protease(s), or an altered exposure of the protease-sensitive sites on the receptors. It will be of particular interest to determine whether the protease(s) that cleaves GP Ib alpha and GP V in platelets is the same as the protease(s) that cleaves receptors from the surface of other activated cells. Receptors also are shed from the surface of activated platelets by the generation of microvesicles from the plasma membrane. These microvesicles appear to contain all of the major membrane glycoproteins but are depleted in those that have been removed from the platelet membrane by proteolytic cleavage. The primary mechanism responsible for the shedding of microvesicles from the surface of platelets stirred with physiological agonists involves activation of calpain, which cleaves components of the membrane skeleton and dissociates it from the plasma membrane GP Ib-IX complex. Microvesicles are present in the circulation and increase under conditions in which platelet activation is known to have occurred. Because they contain functional adhesive receptors and procoagulant activity on their surface, they may function to disseminate procoagulant activity and stabilize the formation of platelet clots.