Integrins and other families of cell adhesion receptors are responsible for platelet adhesion and aggregation, which are essential steps for physiological haemostasis, as well as for the development of thrombosis. The modulation of platelet adhesive properties is the result of a complex pattern of inside-out and outside-in signaling pathways, in which the members of the Rap family of small GTPases are bidirectionally involved. This paper focuses on the regulation of the main Rap GTPase expressed in circulating platelets, Rap1b, downstream of adhesion receptors, and summarizes the most recent achievements in the investigation of the function of this protein as regulator of platelet adhesion and thrombus formation. 1. Introduction The adhesion of circulating blood platelets to the subendothelial matrix exposed upon vessel wall injury represents the initial event of the haemostatic process required to limit hemorrhage. Platelets express several membrane receptors specific for all the major adhesive ligands of the vascular extracellular matrix [1]. Among these, collagen is probably the most important subendothelial matrix component involved in thrombus formation, and platelet adhesion to collagen is associated with a complex pattern of activatory signaling pathways. Integrin α2β1 and glycoprotein VI (GPVI) are the two main platelet receptors for collagen and, in the rheological conditions of low shear rates, typically present in large veins and venules, are sufficient to mediate firm platelet adhesion. At high shear rates, characteristic of small arteries and stenotic vessels, platelets are unable to efficiently interact to exposed collagen fibers, and in these conditions adhesion is preceded by platelet tethering and rolling on the site of injury. This process is mediated by the membrane GPIb-IX-V complex, a platelet-specific receptor for the multimeric glycoprotein von Willebrand factor (VWF). At high shear stress, circulating VWF rapidly interacts with exposed collagen fibers and undergoes a conformational change that allows the interaction with the GPIb-XI-V complex, decelerating platelets and favoring the subsequent stable adhesion mediated by other platelet receptors [2]. The interaction of platelet adhesion receptors with subendothelial matrix components stimulates an intricate pattern of signal transduction pathways, that trigger spreading, secretion of soluble proaggregating molecules, thromboxane A2 (TxA2) synthesis and release, and phosphatydilserine exposure. These events recruit and activate additional circulating platelets to initiate a
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