GPVI

Abstract: At sites of vascular injury, platelets come into contact with the subendothelial extracellular matrix which triggers their activation and the formation of a hemostatic plug. This process is crucial for normal hemostasis, but may also lead to pathological thrombus formation causing diseases such as myocardial infarction or stroke. The initial capture of flowing platelets is mediated by the interaction of the glycoprotein (GP) Ib-V-IX complex with von Willebrand factor (vWF) immobilized on exposed collagens. This interaction allows the binding of the collagen receptor GPVI to its ligand and to initiate cellular activation, a process that is reinforced by locally produced thrombin and soluble mediators released from platelets. These events lead to the shift of beta1 and beta3 integrins on the platelet surface from a low to a high affinity state, thereby enabling them to bind their ligands and to mediate firm adhesion, spreading, coagulant activity, and aggregation. This review summarizes the most important structural and functional properties of these adhesion receptors and briefly discusses their potential as targets for antithrombotic therapy.

Abstract: Platelet adhesion on and activation by components of the extracellular matrix are crucial to arrest post-traumatic bleeding, but can also harm tissue by occluding diseased vessels. Integrin alpha2beta1 is thought to be essential for platelet adhesion to subendothelial collagens, facilitating subsequent interactions with the activating platelet collagen receptor, glycoprotein VI (GPVI). Here we show that Cre/loxP-mediated loss of beta1 integrin on platelets has no significant effect on the bleeding time in mice. Aggregation of beta1-null platelets to native fibrillar collagen is delayed, but not reduced, whereas aggregation to enzymatically digested soluble collagen is abolished. Furthermore, beta1-null platelets adhere to fibrillar, but not soluble collagen under static as well as low (150 s(-1)) and high (1000 s(-1)) shear flow conditions, probably through binding of alphaIIbbeta3 to von Willebrand factor. On the other hand, we show that platelets lacking GPVI can not activate integrins and consequently fail to adhere to and aggregate on fibrillar as well as soluble collagen. These data show that GPVI plays the central role in platelet-collagen interactions by activating different adhesive receptors, including alpha2beta1 integrin, which strengthens adhesion without being essential.

Abstract: The vessel wall contains a continuous lining of endothelium that serves as a barrier between the circulating platelets and the prothrombotic subendothelial matrix (1). Upon vessel injury, the endothelial layer is disrupted and the circulating platelets are exposed to subendothelial proteins such as vWF, collagen, and vitronectin, among others (1). The platelets initially interact with the subendothelium through adhesive receptors, such as GPIb-IX-V receptors, that mediate rolling and tethering of the platelets to vWF at the site of vascular injury. Next, the platelet collagen receptors α2β1 and GPVI mediate a more firm adhesion and cause further platelet activation. These initial interactions with the subendothelium cause the release of contents from the platelet dense granules, which contain platelet agonists such as ADP, and the α-granules, which contain fibrinogen, factor V, and P-selectin (1). The release of the granule contents causes further platelet activation, but it also fuels the coagulation response as a result of the release of factor V and fuels the inflammatory response through the exposure of P-selectin on the platelet surface. The platelet also generates lipid mediators such as thromboxane A2. ADP elicits its effects on the platelet through the P2Y1 and P2Y12 receptors (2), whereas thromboxane A2 activates the thromboxane-prostanoid (TP) receptor on the platelet surface (1). The released dense granule contents cause further platelet activation and recruitment of circulating platelets to the site of injury. Platelets interacting with these mediators also undergo platelet shape change, a process of actin cytoskeletal reorganization that changes the platelets from a disc shape to a round shape with long, filopodial extensions that form a meshwork of platelets in the platelet plug (3). Also, tissue factor is exposed, which initiates the coagulation response that results in formation of thrombin. Thrombin activates platelets via interactions with the proteinase-activated receptor-1 (PAR1) and PAR4 receptors (4) and also cleaves fibrinogen to form fibrin. Fibrin further stabilizes the accumulating platelet plug at the site of injury, resulting in a stable hemostatic plug. Interactions of the platelets with collagen, vWF, ADP, thromboxane A2, and thrombin cause intracellular platelet signaling that leads to the activation of the heterodimeric integrin αIIbβ3, also known as the fibrinogen receptor (5). The intracellular platelet signaling from these agonists causes the fibrinogen receptor to change from a low-affinity state to a high-affinity state that binds fibrinogen (6). Fibrinogen binds to the platelets via the activated fibrinogen receptor, and this cross-linking of platelets to fibrinogen results in platelet aggregates that accumulate and arrest bleeding at the site of injury (Figure ​(Figure1).1). Thus, platelet activation is the product of many signals originating from many receptors, which each contribute to the formation of a platelet plug. Figure 1 The hemostatic process. Upon vessel injury, platelets roll and become tethered to the vessel wall by interactions with vWF and collagen (noted as black strands). These interactions cause platelet shape change, and release of ADP from dense granules. The ... Pathophysiologic conditions, such as atherosclerotic plaque rupture, can lead to aberrant platelet activation resulting in arterial thrombosis, which can cause myocardial infarction and ischemic stroke (6). The importance of ADP in this process has been demonstrated both by antiplatelet drugs that target the P2Y12 receptor (2) and by patients with dysfunctional P2Y12 receptors (7). Antagonism of the P2Y12 receptor with either ticlopidine or clopidogrel is clinically effective in the prevention of myocardial infarction, ischemic stroke, and vascular death (8). Despite the established role of the P2Y12 receptor in the hemostatic response, the full implications of P2Y12 receptor antagonism in the prevention of thrombosis remain incompletely understood. It is hoped that more clinically effective P2Y12 antagonists will prevent the incidence of ischemic events that stem from aberrant platelet activation and therefore will be used as improved and suitable treatments for thrombosis.