Shear stress and von Willebrand factor in health and disease.

Blood flow in the circulation creates shear stress that affects cell functions and cell-cell interactions. Recent studies reveal that shear stress is also critical in the homeostasis of the plasma glycoprotein von Willebrand factor (vWF). Because of its large molecular size, vWF has a flexible conformation that is uniquely responsive to shear stress. Exposure to shear stress causes conformational unfolding of vWF, enhancing its susceptibility to cleavage by a plasma zinc metalloprotease (a disintegrin and metalloprotease with thrombospondin type 1 motif [ADAMTS13]). In the absence of ADAMTS13, shear stress increases the capacity of vWF to support platelet aggregation. In normal individuals, a balance between endothelial secretion of an ultralarge form of vWF and intravascular proteolysis determines the size distribution of vWF multimers that seems to be optimum for hemostasis without imposing the risk of unwarranted platelet aggregation. In type 2A (group 2) von Willebrand disease, the mutant vWF is excessively susceptible to cleavage by ADAMTS13, resulting in a decrease of large vWF multimers and bleeding diathesis. In patients with aortic stenosis or the hemolytic-uremic syndrome, abnormally high levels of shear stress across the stenotic valve or in the microcirculation inflicted with thrombosis may promote cleavage of vWF by ADAMTS13, contributing to the loss of large multimers commonly observed among these patients. Conversely, a deficiency in ADAMTS13 because of genetic mutations or autoimmune inhibitors causes vWF- and platelet-rich microvascular thrombosis characteristic of thrombotic thrombocytopenic purpura.