Adhesion-dependent signalling and the initiation of haemostasis and thrombosis

Abstract

Cell-cell and cell-extracellular matrix adhesion are critical aspects of platelet function, regulating interactions between circulating platelets in the bloodstream with the blood vessel wall. In haemostasis, platelets adhere to the subendothelial matrix of a damaged vessel, spread over the surface and recruit additional platelets within a developing platelet aggregate or thrombus. In addition to this normal physiological response, platelet adhesion is critical in the pathological process of thrombosis, where circulating platelets adhere to sclerotic lesions or undergo shear-induced aggregation within vessels occluded by atherosclerotic plaque. Under these circumstances, the resulting thrombus may result in acute myocardial infarction or stroke. Each stage of platelet adhesion and aggregation in haemostasis and thrombosis is regulated by specific cell surface adhesion receptors. Interestingly, most of the adhesive receptors studied in detail have been found not only to regulate contact adhesion, but also to transduce intracellular signals that activate the cell, initiate post-adhesion cellular events, and regulate the adhesive function of other receptors. Platelet activation triggers the cytoskeletal rearrangements that control cell shape change, spreading, secretion, aggregation and contraction. This review will focus on adhesiondependent signalling induced by the platelet surface receptor, the glycoprotein (GP) Ib-IX-V complex, that initiates thrombus formation in both haemostasis and thrombosis under conditions of high shear blood flow. Emerging evidence suggests GP Ib-IX-V-dependent signalling may involve receptor cross-linking and the cytoplasmic signalling protein, 14-3-3 ξ.