New insights into von Willebrand disease and platelet function

Regulation of binding between von Willebrand factor (VWF) and the platelet receptor glycoprotein (GP) Ibα is one of the key steps in controlling hemostasis and thrombosis. On vascular injury at sites of high shear rates, the GPIbα interaction with subendothelial-bound VWF will initiate the tethering of circulating platelets to the vessel wall. Tethered platelets subsequently roll on the damaged vessel wall, a process that is amplified by the activation of the platelet integrin αΙΙbβ3 (GPIIb/IIIa). The initial tethering to VWF is rapidly followed by platelet binding to collagen through specific receptors (GPVI and α2β1), leading to firm adhesion, activation, and additional stable bonds mediated by αΙΙbβ3. The above described interactions can result in two distinct processes: physiological hemostasis and pathological thrombosis. Furthermore, VWF carries coagulation factor VIII, which is involved in thrombin formation that in addition to activating platelets, mediates fibrin formation and has several other actions. The importance of VWF in hemostasis is well known in patients suffering from von Willebrand disease (VWD) who present with a defect in both platelet plug and fibrin formation. Type 2B VWD is of special interest as it may provide further insight into the mechanism by which VWF promotes the adhesion of platelets to a thrombogenic surface under conditions of high shear stress. The variant phenotypic manifestations in patients affected with type 2B VWD, however, have raised the question of locus heterogeneity in VWD as a consequence of, for example, additional defects in receptor or signaling proteins mediating platelet adhesion and aggregation. Indeed, quite a few polymorphisms of platelet receptors have been associated with increased bleeding in VWD. However, many aspects of the disease remain to be elucidated. For instance, thrombin and platelet procoagulant activity may be important counterplayers to determine the severity of the bleeding complications associated with VWD.