VWF - Mechanisms of Regulation

项目概要 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 均介导 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。 1型冯 血友病 (VWD) 是最常见的 VWD 亚型，伴有 VWF 数量缺乏。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 VWF 半衰期显着缩短（1-3 小时 vs 12-16 小时），这严重影响了 DDAVP 的功效 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。 VWF 快速清除严重损害 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及其释放 1 型和 1C VWD 给药 DDAVP 后的清除率。这可能会减少对 在患者或受影响的家庭成员中进行 DDAVP 试验。导致 VWF 减少的潜在机制 患者的生存率在很大程度上仍不确定。许多研究表明 VWF 之间存在联系 糖基化和 VWF 清除。最近使用合并的方法确定了 VWF 的聚糖组成 来自健康捐献者的血浆。然而，个体健康对照者和 VWD 患者的 VWF 聚糖变异 还没有研究过。我们的假设是 1C 型 VWD 受试者的 VWF 糖基化会发生改变 与健康对照相比，导致 VWF 从血浆中的清除率增加。我们建议 在一大群健康对照者和特征明确的 VWF 患者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。该项目针对的是 改善 1 型 VWD 患者的治疗并增强我们对 VWF 聚糖的科学知识 变异性以及与 VWF 清除的联系。

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.