New perspectives on von Willebrand factor functions in hemostasis and thrombosis

The adhesive protein, von Willebrand factor (VWF), mediates the initiation and progression of thrombus formation at sites of vascular injury by means of specific interactions with extracellular matrix components and platelet receptors. The essential biologic properties of VWF have been elucidated, with progress particularly in the areas of genetic regulation, biosynthesis, and specific bimolecular interactions. The three-dimensional structure of selected domains has been solved, but our understanding of detailed structure-function relationships is still fragmented, partly because of the complexity and size of the VWF molecule. The biomechanical properties of the interaction between the VWF A1 domain and the platelet receptor glycoprotein (GP) Ibalpha also are better known, but we can still only hypothesize how this adhesive bond can oppose the fluid dynamic effects of rapidly flowing blood to initiate thrombus formation and contribute to platelet activation. Elucidating the details of VWF and GPIbalpha function will lead to a more satisfactory definition of the role of platelets in atherothrombosis, since hemodynamic forces greatly influence responses to vascular injury in stenosed and partially occluded arteries. Progress in this direction is also aided by rapidly expanding novel information on the mechanisms that regulate VWF multimer size in the circulation, a topic of relevance to explain microvascular thrombosis and, perhaps, arterial thrombosis in general. Developments in these areas of research will refine our understanding of the role played by VWF in vascular biology and pathology.