VWF - Mechanisms of Regulation

项目摘要 血浆血管性血友病因子（VWF）水平的调节对于止血至关重要，因为VWF既介导 血小板粘附在血管损伤部位，并作为凝血因子VIII的载体蛋白。一型冯 维勒布兰德病（Willebrand disease，VWD）是最常见的VWD亚型，VWF含量缺乏。的 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vs 12-16小时），严重影响DDAVP的疗效 治疗DDAVP将VWF从内皮细胞储存颗粒释放到血浆中，是最常见的 1型VWD的治疗。快速VWF清除实质上损害了1C型患者的治疗。1C型 通过增加的VWF前肽（VWFpp）与VWF抗原（VWF：Ag）的比率来鉴定患者。我们的假设 血浆VWFpp和VWFpp/VWF：Ag的测定可用于预测VWF的释放， 1型和1C型VWD中DDAVP给药后的清除率。这可能会减少对 在患者或受影响家庭成员中进行的DDAVP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不确定。许多研究表明，VWF与 糖基化和VWF清除。VWF的聚糖组成最近使用合并的 健康捐献者的血浆。然而，在个体健康对照和VWD患者中，VWF聚糖变异 尚未被研究。我们的假设是1C型VWD受试者的VWF糖基化改变， 与健康对照组相比，VWF曲线导致血浆中VWF清除增加。我们建议 在一个健康对照和特征明确的VWF患者的大队列中系统地定义了这种变异 并将VWF糖基化的改变与血浆清除率的增加联系起来。该项目针对 改善1型VWD患者的治疗，并提高我们对VWF聚糖的科学认识 变异性和与VWF清除率的联系。

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.