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

冯·维勒布兰德病衰老与出血相关性 (VWD ABC) 研究

• 批准号: 10443730
• 负责人: Craig D Seaman
• 金额: $ 16.56万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443730
• 关键词: Adult; Affect; Age; Aging; Assessment tool; Bioinformatics; Biology; Blood; Blood Coagulation Disorders; Blood specimen; Cardiovascular Diseases; Caring; Clinic Visits; Clinical; Clinical Research; Clinical Trials; Correlation Studies; Cross-Sectional Studies; DDAVP; DNA; Data; Diagnosis; Elderly; Enrollment; Ensure; Epidemiology; Estrogen Therapy; Evidence based practice; Factor VIII; Factor VIII-Related Antigen; Future; Genes; Genetic; Goals; Healthcare; Hematologist; Hematology; Hemophilia A; Hemorrhage; Hemostatic function; Individual; Inherited; Investigation; Knowledge; Laboratories; Longitudinal observational study; Medical; Mentored Patient-Oriented Research Career Development Award; Mentorship; Multicenter Studies; Mutation; Normal Range; Pathogenicity; Patient Care; Patients; Phenotype; Physicians; Play; Population; Principal Investigator; Procedures; Process; Randomized; Recording of previous events; Research; Research Activity; Research Infrastructure; Risk; Risk Factors; Role; Sampling; Scientist; Symptoms; Testing; Thrombosis; Training; age effect; age related; base; biobank; comorbidity; cost; epidemiology study; experience; genomic locus; improved; insight; multiple chronic conditions; mutational status; older patient; prophylactic; research study; safety outcomes; skills; treatment center; trial comparing; unnecessary treatment; von Willebrand Disease; von Willebrand Factor; wasting

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. !

项目摘要 我是一名对临床研究充满热情的学术血液学家。我的主要目标是成为一个 成功的独立医师科学家在生物学，流行病学和循证方面具有专业知识 罕见出血疾病的实践。更具体地说，我的长期研究目标是更好地定义 遗传性出血疾病的年龄和与年龄有关的状况，例如冯·威勒氏病（VWD）。这 K23奖将使我能够发展为多中心临床首席研究员所必需的技能 研究，接受过流行病学研究的培训，并精通 生物信息学分析遗传数据。我已经组建了一个杰出的指导团队，包括 血液学和流行病学，以帮助我实现这些目标。我的临床研究活动将进行 在HCWP，受益于优秀的研究基础设施。 该提案的目的是确定年龄对von Willebrand因素（VWF）水平的影响和 1型VWD患者的出血风险。我们将执行多中心横断面研究 诊所期间参与的血友病治疗中心（n = 7）的1型VWD患者，年龄在18岁及以上的患者 访问。注册后，将管理凝结的MCMDM-1 VWD出血评估工具 将获得血液样本。实验室测试包括VWF抗原（VWF：AG）水平，VWF Ristocetin 辅因子活性，VIII因子活性和血型。 DNA将获得额外的血液样本 VWF基因测序和分析的分离。我们假设年龄与增加有关 VWF：1型VWD患者的AG水平和较低的凝结MCMDM-1 VWD出血评分。在 此外，我们假设多种菌度部分解释了年龄与VWF之间的关联：Ag水平。 我们还建议VWF：Ag水平部分解释了年龄与凝结MCMDM-1之间的关联 VWD出血分数。最后，我们期望年龄对VWF的影响：Ag水平和凝结的MCMDM-1 VWD 在具有致病性VWF突变的患者中，出血得分较弱。 老年1型VWD患者中出血风险的鉴定对于提供适当的 对患者的医疗保健。对年龄较大的1型VWD患者进行VWD特异性治疗 归一化的VWF水平可能有害，使患者处于血栓形成的危险中。因此，调查 迫切需要年龄对VWF水平的影响和VWD患者的出血风险。这项研究的结果将 为未来的R级独立研究提供初步数据：1）一项纵向观察研究 评估VWD患者年龄的出血风险； 2）比较出血和安全结果的临床试验 在1型VWD患者中，有正常的VWF水平正在接受侵入性手术为VWD 治疗或没有VWD治疗； 3）生物验证样品的基因测序以鉴定候选非VWF 基因座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。 呢