Structure and multiple functions of von Willebrand factor.

Since the first description of a patient with von Willebrand disease (VWD) back in 1926, significant advances have been made in understanding the biology of von Willebrand factor (VWF). Under normal conditions, in vivo biosynthesis of VWF is restricted to endothelial cells and megakaryocytes only. This biosynthesis involves complex post-translational modifications (including glycosylation and multimerization) which play a key role in enabling the hemostatic functions of VWF. As a result, VWF circulates in normal plasma as a series of heterogeneous multimers that can modulate tethering of platelets and primary hemostasis at sites of vascular injury. In addition, VWF also influences secondary hemostasis by serving as a chaperone molecule and protecting factor VIII from proteolysis and premature clearance. The molecular mechanisms underlying the pro-hemostatic functions of VWF have been comprehensively characterized. These insights serve to underpin the current classification of different VWD subtypes. Interestingly, accumulating evidence over the past decade has identified an array of new ligands that are able to bind to VWF. Consistent with these data, recent studies have further suggested a series of novel and non-hemostatic biological functions for VWF. These include potential roles for VWF in regulating inflammation, wound healing, angiogenesis and tumor cell metastasis. Further research in the coming years will be required to determine the clinical significance of these non-hemostatic roles of VWF. Defining the molecular mechanisms involved may offer exciting opportunities to develop novel anti-VWF targeted treatment approaches for important unmet clinical needs.