VWF - Mechanisms of Regulation

项目摘要 血浆von Willebrand因子(Vwf)水平的调节是止血的关键，因为vwf既有中介作用，也有中介作用。 血管损伤部位的血小板黏附是凝血因子VIII的载体蛋白。1型von 威勒布兰德病(VWD)是最常见的VWD亚型，其数量缺乏。这个 血浆VWF存活率降低是一种新的VWD机制，称为1C型。1C型VWD患者有一个 显著降低VWF半衰期(1-3小时对12-16小时)，这严重影响DDAVP的疗效 治疗。DDAVP将血管内皮细胞储存颗粒中的VWF释放到血浆中，是最常见的 1型VWD的治疗。VWF的快速清除严重影响了1C型患者的治疗。1C型 通过增加VWF前肽(VWFpp)与VWF抗原(VWF：Ag)的比率来识别患者。我们的假设 血浆VWFpp和VWFpp/VWF：Ag的测定可用于预测VWF及其受体的释放 1型和1C型VWD患者服用DDAVP后的清除率。这可能会减少对 DDAVP在患者或受影响的家庭成员中的试验。导致VWF降低的潜在机制 患者的存活率在很大程度上仍未确定。多项研究表明，VWF与 糖基化和VWF清除。VWF的多糖组成最近被用Pooled 来自健康捐献者的血浆。然而，VWD患者和健康对照个体的VWF糖链变异 还没有被研究过。我们的假设是，1C型VWD受试者将有VWF糖基化改变 与健康对照组相比，VWF从血浆中的清除增加。我们建议 在一大群健康对照和特征良好的VWF患者中系统地定义这种变异 VWF糖基化的改变与血浆清除量的增加有关。该项目针对的是 改善1型VWD患者的治疗并增强我们对VWF多糖的科学知识 可变性和与VWF通关的联系。

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.