[Platelet--vessel wall interactions]

Abstract

The vascular endothelium is a thromboresistant surface, allowing the free flowing of blood cell elements. Platelets are predominantly involved in the rapid response to a vascular lesion, exposing the underlying thrombogenic subendothelium and leading to initiation of thrombus formation. Thrombus growth requires on the one hand, the recruitment of circulating platelets to the luminal side of the thrombus and on the other hand, the assembly of the proteins of the blood coagulation cascade on the platelet catalytic surface leading to thrombin formation. High shear forces are necessary for the dual role of von Willebrand factor (VWF) in the initiation of platelet thrombus formation and in its growth and stabilization. In hemodynamic conditions, platelet adhesion depends on the interaction between VWF and the platelet receptor glycoprotein Ib (GPIb). This interaction is the only one able to resist to the high shear rates that prevail in arterioles, the microcirculation or stenosed arteries. Thereafter, the interaction between VWF and the alphaIIbbeta3 integrin allows the definitive arrest of platelets and induces thrombus formation. Thus, high shear forces by themselves are able to induce platelet activation/aggregation, without added exogenous agonist. VWF is synthesised by endothelial cells as a series of multimers of different sizes. The multimers with the highest molecular weight, the so-called ultra-large multimers, are strongly thrombogenic by their increased ability to bind platelet GPIb and to induce the formation of circulating aggregates. These ultra-large multimers are normally cleaved by the ADAMTS13 metalloprotease into smaller multimers which are also less thrombogenic. The in vivo proteolysis of VWF by ADAMTS13 depends on the high shear rates, which increase the opening of multimers anchored to the endothelial cell layer and the exposure of the cleavage site of VWF by ADAMTS13. An ADAMTS13 deficiency thus likely would result in the accumulation of ultra-large multimers on the endothelial surface, which retains platelets on the activated endothelium and results in micro-thrombi formation, as seen in thrombotic thrombocytopenic purpura. Platelet-VWF interactions are also involved in inflammation. Activation of endothelial cells induces the release of VWF from the Weibel-Palade bodies as well as the surface expression of VWF and P-selectin. These molecules allow leukocyte and platelet rolling on endothelial cells, and expression of E-selectin, VCAM-1 and other adhesion molecules. Recently, it has been shown that activated platelets allow transient activation of intact, non stimulated endothelial cells, thus increasing the inflammation process. VWF and platelet P-selectin have been shown to be essential to this process. Thus, platelet--vessel wall interactions are involved in thrombosis and inflammation essentially via VWF.