The Von Willebrand Disease Aging and Bleeding Correlation (VWD ABC) Study

项目摘要 我是一名学术血液学家，对临床研究充满热情。我的首要目标是成为一名 成功、独立的内科医生-科学家，在生物学、流行病学和循证医学方面具有专业知识 罕见出血性疾病的实践。更具体地说，我的长期研究目标是更好地定义 遗传性出血性疾病的年龄和与年龄相关的疾病，如von Willebrand病(VWD)。这 K23奖将让我发展作为多中心临床首席研究员所需的技能 研究性学习，接受流行病学研究方面的培训，并熟练使用 生物信息学来分析基因数据。我已经组建了一支优秀的导师团队，其中包括 血液学和流行病学，帮助我实现这些目标。我的临床研究活动将在 并受益于出色的研究基础设施。 这项建议的目标是确定年龄对von Willebrand因子(VWF)水平的影响，以及 1型VWD患者的出血风险。我们将进行一项多中心、横断面研究 参加血友病治疗中心的1型VWD患者，年龄18岁及以上(N=7) 来访。注册后，将使用简化的MCMDM-1 VWD出血评估工具 血液样本将会被采集。实验室检测包括VWF抗原(VWF：Ag)水平、VWF凝集素 辅因子活性、第八因子活性和血型。将获得额外的血液样本进行DNA检测 用于VWF基因测序和分析的分离株。我们假设年龄与年龄的增加有关 1型VWD患者的VWF：Ag水平和凝聚型MCMDM-1 VWD出血评分较低。在……里面 此外，我们假设多发病部分解释了年龄和VWF：Ag水平之间的关联。 我们还提出，VWF：Ag水平部分解释了年龄和浓缩的MCMDM-1之间的联系 血管性血友病出血评分。最后，我们预测了年龄对VWF：Ag水平和浓缩MCMDM-1 VWD的影响 在那些具有致病性VWF突变的人中，出血评分较低。 识别老年1型血管性血友病患者的出血风险是提供适当的 向受影响的病人提供医疗服务。对老年1型VWD患者进行VWD特异性治疗 正常化的VWF水平可能是有害的，将患者置于血栓形成的风险中。因此，对该事件的调查 年龄对VWD患者的VWF水平和出血风险的影响是迫切需要的。这项研究的结果将 为未来几项R级独立研究提供初步数据：1)纵向观察性研究 评估VWD患者的出血风险与年龄；2)比较出血和安全性结果的临床试验 在接受侵入性手术的VWF水平正常的1型VWD患者中随机分为VWD组 治疗或不治疗VWD；以及3)生物信息库样本的基因测序以确定候选的非VWF 并探索它们如何与年龄对VWF水平和出血风险的影响相互作用。 好了！

Project Summary I am an academic hematologist passionate about clinical research. My primary goal is to become a successful, independent physician-scientist with expertise in the biology, epidemiology, and evidence-based practice of rare bleeding disorders. More specifically, my long-term research goal is to better define the role of age and age-related conditions in hereditary bleeding disorders, such as von Willebrand disease (VWD). This K23 award will allow me to develop the skills necessary to act as a principal investigator for multicenter clinical research studies, become trained in epidemiological research, and become proficient in the use of bioinformatics to analyze genetic data. I have assembled an outstanding mentorship team, including experts in hematology and epidemiology, to help me achieve these goals. My clinical research activities will be conducted at HCWP and benefit from the excellent research infrastructure. The goal of this proposal is to determine the effect of age on von Willebrand factor (VWF) levels and bleeding risk in patients with type 1 VWD. We will perform a multicenter, cross-sectional study enrolling patients with type 1 VWD, age 18 and older, at participating Hemophilia Treatment Centers (N=7) during clinic visits. Following enrollment, the condensed MCMDM-1 VWD bleeding assessment tool will be administered and blood samples will be obtained. Laboratory tests include VWF antigen (VWF:Ag) level, VWF ristocetin cofactor activity, factor VIII activity, and blood type. An additional blood sample will be obtained for DNA isolation for VWF gene sequencing and analysis. We hypothesize that age is associated with increased VWF:Ag levels and lower condensed MCMDM-1 VWD bleeding scores in patients with type 1 VWD. In addition, we hypothesize that multimorbidity partially explains the association between age and VWF:Ag levels. We also propose that VWF:Ag levels partially explain the association between age and condensed MCMDM-1 VWD bleeding scores. Finally, we expect the effect of age on VWF:Ag levels and condensed MCMDM-1 VWD bleeding scores is weaker among those with a pathogenic VWF mutation. The identification of bleeding risk in elderly type 1 VWD patients is essential for providing appropriate medical care to affected patients. Administering VWD-specific therapy to older type 1 VWD patients with normalized VWF levels may be harmful, placing patients at risk for thrombosis. Thus, investigation into the effect of age on VWF levels and bleeding risk in VWD patients is sorely needed. The results from this study will provide preliminary data for several future R-level independent studies: 1) a longitudinal observational study assessing bleeding risk with age in VWD patients; 2) a clinical trial comparing bleeding and safety outcomes among type 1 VWD patients with normalized VWF levels undergoing invasive procedures randomized to VWD therapy or no VWD therapy; and 3) gene sequencing of biorepository samples to identify candidate non-VWF loci and explore how they interact with the effect of age on VWF levels and bleeding risk. !