Regulating interactions between von Willebrand factor and platelets

The formation of thrombi is a complex process involving many players, including biological agents and physical parameters. Among the several thrombogenic proteins, von Willebrand factor (VWF) plays a major role in the initiation of thrombus formation. This adhesive multimeric protein functions as a molecular bridge between the subendothelial matrix and the platelet glycoprotein (GP) Ib/IX/V complex. Indeed, FVW-GPIb/IX/V interactions allow the recruitment of circulating platelets to the site of injury and the initiation of thrombus formation. VWF also promotes platelet aggregation and thrombus growth by involving platelet integrin alpha(IIb)beta(3). Given the co-existence of VWF and platelets in the circulation, this implies that there must be regulatory mechanisms that prevent premature formation of VWF-platelet aggregates that could occlude the vasculature. Indeed, several mechanisms to limit VWF-platelet interactions have been identified (i) at the level of VWF by conformational modifications induced by shear stress; (ii) by interactions with endothelial proteins (Galectin-1, Galectin-3, osteoprotegerin); (iii) by ADAMTS13-mediated proteolysis of very large VWF multimers; or (iv) by plasmabased inhibitors of VWF-platelet interactions. The current review will provide an overview of novel insights of the regulatory pathways at the level of VWF that are directed to prevent premature binding of VWF to platelets.