Novel functions for Von Willebrand factor

For many years, it has been known that VWF interacts with FVIII, collagen and platelets. In addition, the key roles played by VWF in regulating normal hemostasis have been well defined. However, accumulating recent evidence has shown that VWF can interact with a diverse array of other novel ligands. To date, more than 60 different binding partners have been described, with interactions mapped to specific VWF domains in some cases. Although the biological significance of these VWF binding interactions has not been fully elucidated, recent studies have identified some of these novel ligands as regulators of various aspects of VWF biology, including biosynthesis, proteolysis and clearance. Conversely, VWF-binding has been shown to directly impact the functional properties for some of its ligands. In keeping with those observations, exciting new roles for VWF in regulating a series of non-hemostatic biological functions has also emerged. These include inflammation, wound healing, angiogenesis, and bone metabolism. Finally, recent evidence supports the hypothesis that the non-hemostatic functions of VWF directly contribute to pathogenic mechanisms in a variety of diverse diseases including sepsis, malaria, sickle cell disease and liver disease. In this manuscript, we review the accumulating data regarding novel ligand interactions for VWF and critically assess how these interactions may impact cellular biology. In addition, we consider the evidence that non-hemostatic VWF functions may contribute to the pathogenesis of human diseases beyond thrombosis and bleeding.