von Willebrand factor: at the crossroads of bleeding and thrombosis

Abstract

Hemostasis and thrombosis represent two sides of the same coin. Hemostasis maintains blood fluidity in the vascular system while allowing for rapid thrombus formation to prevent excessive hemorrhage after blood vessel injury. Thrombosis is a pathologic extension of the normal hemostatic mechanism, occurring when unwanted clot formation develops in certain pathological situations. The molecular mechanisms underlying both phenomena are fundamentally identical. One of the key players in both processes is the plasma glycoprotein von Willebrand factor, which perfectly illustrates this duality between hemostatic and thrombotic mechanisms. The purpose of this review is to discuss novel findings on the role of von Willebrand factor at this interface, and how some of these findings may help develop new therapeutic strategies.

Figure 1. VWF: A Janus protein in bleeding and thrombosis

The hemostatic system is designed to react rapidly upon vascular damage in order to minimize blood loss, and needs tight regulation to prevent thrombotic occlusion of the vessels. VWF is a key player of the hemostatic system, illustrated by its liaison with both hemorrhagic and thrombotic conditions. In the present review, novel findings on the role of VWF at this interface between bleeding and thrombosis are being discussed.

Figure 2. Effect of deficient collagen binding on VWF function in hemostasis and thrombosis in a murine model

VWF-deficient mice were left untreated or injected with murine Vwf cDNA encoding for wild-type or a collagen binding mutant VWF. Four days after injection, when plasma expression of VWF was stable, mice were challenged in a tail-bleeding time assay (A) or in a ferric-chloride induced thrombosis model. Mice expressing the VWF molecule unable to bind to collagens were able to correct their bleeding time but had significantly prolonged occlusion time in arterioles. Platelet accumulation in vessels is visualized in green fluorescence. This research was originally published in Blood. Marx I et al. Blood. 2008;112:603–609. © the American Society of Hematology.

Figure 3. Events associated with shear stress-induced conformational changes in VWF

VWF circulates in a globular conformation with its platelet-binding site being inaccessible. In addition, the ADAMTS13-cleavage site in the A2 domain in unavailable. Both parameters protect VWF from premature platelet interactions and ADAMTS13-mediated degradation. Exposure to increased shear stress unfolds the protein, allowing platelet binding and ADAMTS13 cleavage. In addition, buried methionine residues become exposed, which are sensitive to oxidation by reactive oxygen species. Oxidized VWF displays resistance against ADAMTS13 proteolysis and enhanced platelet binding. Platelet binding is further enhanced by the formation of novel disulfide-bridges in the VWF C-domains. Shear stress-induced disulfide bridging is downregulated by thiol reductase activity that resides in the C-terminal region of ADAMTS13.