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: 10656322
• 负责人: Craig D Seaman
• 金额: $ 17.18万
• 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/10656322
• 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; Mutation; Normal Range; Pathogenicity; Patient Care; Patients; Phenotype; Physicians; Population; Predisposition; 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; biobank; candidate identification; comorbidity; cost; epidemiology study; experience; genomic locus; improved; insight; multiple chronic conditions; mutational status; older patient; participant enrollment; prophylactic; research study; risk mitigation; 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 我是一名学术血液学家，热衷于临床研究。我的主要目标是成为 成功的，独立的医生，科学家，在生物学，流行病学和循证医学方面的专业知识， 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 年龄和年龄相关的遗传性出血性疾病，如血管性血友病（VWD）。这 K23奖将使我能够发展作为多中心临床研究的主要研究者所需的技能。 研究，成为流行病学研究的培训，并成为熟练使用 生物信息学来分析基因数据。我组建了一个优秀的导师团队，包括以下方面的专家： 血液学和流行病学来帮助我实现这些目标。我的临床研究活动将在 在HCWP，并受益于优秀的研究基础设施。 本提案的目的是确定年龄对血管性血友病因子（VWF）水平的影响， 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， 临床期间参与血友病治疗中心的18岁及以上1型VWD患者（N=7） 探访入组后，将使用浓缩MCMDM-1 VWD出血评估工具 并采集血样。实验室检查包括VWF抗原（VWF：Ag）水平、VWF Ristoconstructive 辅因子活性、因子VIII活性和血型。将获得额外的血液样本用于DNA检测 分离用于VWF基因测序和分析。我们假设年龄与增加的 1型VWD患者的VWF：Ag水平和较低的浓缩MCMDM-1 VWD出血评分在 此外，我们假设多聚体部分解释了年龄和VWF：Ag水平之间的关系。 我们还提出VWF：Ag水平部分解释了年龄与MCMDM-1浓缩之间的关系。 VWD出血评分。最后，我们期待年龄对VWF：Ag水平和浓缩MCMDM-1 VWD的影响。 出血评分在具有致病性VWF突变的患者中较弱。 识别老年1型VWD患者的出血风险对于提供适当的 为受影响的患者提供医疗服务。对老年1型VWD患者给予VWD特异性治疗， 正常的VWF水平可能是有害的，使患者处于血栓形成的风险中。因此，调查 年龄对VWD患者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患者随年龄变化的出血风险; 2）比较出血和安全性结局的临床试验 在随机接受VWD治疗的VWF水平正常的1型VWD患者中， 治疗或无VWD治疗;和3）生物储存库样品的基因测序以鉴定候选非VWF 位点，并探讨它们如何与年龄对VWF水平和出血风险的影响相互作用。 !