MOLECULAR IMPACT OF VWF ON CLINICAL VWD

项目1将包括对血管性血友病患者的多机构研究，并将进行 这些患者的临床评估和1）确定家庭内低或异常VWF的连锁，2） 确定VWF基因中可能导致这些临床表现的基因突变，或3）确定 由VWF基因外的其他遗传位点引起的可遗传异常VWF的频率。候选 可能导致这种情况的基因将通过项目3和项目4进行鉴定。当遗传性VWF突变 确定，项目2将表达突变VWF，并确定潜在的病理生理机制， 体外和体内。目的1将确定VWF基因突变的频率在患者的临床表现， VWD的诊断，并将这些与他们的实验室测试以及临床评分系统相关联， 修改了欧盟VWD研究中使用的方法。它将决定基因谱 导致3型VWD的突变（或其杂合携带者不同于VWF连锁中鉴定的突变） 1型VWD。目的2将确定导致变异的突变，2型VWD，并确定 临床出血症状与用于研究1型患者的评分系统的相似性。临床 将进行实验室表型分析，以对比受影响的连锁家族的异常程度 成员目标3将确定由血浆清除率增加引起的VWD的频率， 通过比较VWF前肽（VWFpp）与VWF的血浆水平来检测， 由DDAVP发布，并将确定O型血和非O型血个体之间的差异。 由于据报道VWD在月经过多的女性中很常见，目标4将研究 与年龄匹配的对照组相比，这些妇女的VWF低或异常。在那些减少或异常 VWF，我们将确定突变率和突变分布是否与1型中确定的相似 VWD。项目1将使人们更好地了解临床VWD的范围和影响， 在临床和研究实验室中检测到。

Project 1 will consist of a multi-institutional study of patients with von Willebrand disease and will perform a clinical assessment of these patients and 1) determine the linkage of low or abnormal VWF within families, 2) determine genetic mutations in the VWF gene that could result in these clinical manifestations or 3) identify the frequency of inheritable abnormal VWF caused by other genetic loci residing outside the VWF gene. Candidate genes that might cause this will be identified through Projects 3 and 4. When genetic VWF mutations are identified, Project 2 will express the mutant VWF and define the underlying pathophysiologic mechanism(s) in vitro and in vivo. Aim 1 will identify the frequency of VWF gene mutations in patients with the clinical diagnosis of VWD and correlate these to their laboratory testing as well as a clinical scoring system that is a modification of the one used in the European Union Study of VWD. It will determine if the spectrum of genetic mutations causing type 3 VWD (or it's heterozygous carriers differs from those mutations identified in VWFlinked type 1 VWD. Aim 2 will identify the mutations causing variant, type 2 VWD and determine the penetrance of clinical bleeding symptoms with the scoring system used to study type 1 patients. Clinical laboratory phenotyping will be performed to contrast the degree of abnormality in affected, linked family members. Aim 3 will determine the frequency of VWD that is caused by increased plasma clearance that can be detected by comparing plasma levels of the VWF propeptide (VWFpp) to VWF, identifying clearance of VWF released by DDAVP, and will determine the differences between these in blood group O and non-O individuals. Since VWD has been reported to be common in women with menorrhagia, Aim 4 will study the prevalence of low or abnormal VWF in these women compared to age-matched controls. In those with reduced or abnormal VWF, we will determine if the mutation rate and distribution of mutations is similar to those identified in type 1 VWD. Project 1 will lead to a greater understanding of the scope and impact of clinical VWD and its ability to be detected in the clinical and research laboratory.