VWF - Mechanisms of Regulation

项目总结

Project Summary The regulation of plasma von Willebrand factor (VWF) level is critical for hemostasis, as VWF both mediates platelet adhesion at sites of vascular injury and serves as carrier protein for coagulation factor VIII. Type 1 von Willebrand disease (VWD) is the most common VWD subtype with quantitative deficiency of VWF. The reduced survival of plasma VWF is a novel VWD mechanism, termed type 1C. Type 1C VWD patients have a significantly decreased VWF half-life (1-3 hrs vs 12-16 hrs), which severely impacts the efficacy of DDAVP treatment. DDAVP releases VWF from endothelial cell storage granules into plasma and is the most common treatment in type 1 VWD. Rapid VWF clearance substantially impairs therapy of type 1C patients. Type 1C patients are identified by increased VWF propeptide (VWFpp) to VWF antigen (VWF:Ag) ratio. Our hypothesis is that the assay of plasma VWFpp and VWFpp/VWF:Ag can be used to predict the release of VWF and its clearance rate after DDAVP administration in types 1 and 1C VWD. This could potentially reduce the need for DDAVP trials in patients or affected family members. The underlying mechanisms causing reduced VWF survival in patients remain largely undefined. A number of studies have suggested a link between VWF glycosylation and VWF clearance. The glycan composition of VWF was recently determined using pooled plasma from healthy donors. However, VWF glycan variation in individual healthy controls and VWD patients has not been studied. Our hypothesis is that type 1C VWD subjects will have an altered VWF glycosylation profile compared to healthy controls resulting in increased VWF clearance from plasma. We propose to systematically define this variation in a large cohort of healthy controls and well-characterized VWF patients and link alteration of VWF glycosylation with increased clearance from plasma. This project is directed at improving treatment in type 1 VWD patients as well as enhancing our scientific knowledge of VWF glycan variability and the link to VWF clearance.