Abnormal Bleeding Risk in Female Hemophilia A Carriers

女性 A 型血友病携带者的异常出血风险

• 批准号: 10471945
• 负责人: Peter H Cygan
• 金额: $ 17.27万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471945
• 关键词: Activated Partial Thromboplastin Time measurement; Address; Adolescent; Adult; Advocate; Affect; Alleles; Anticoagulants; Antigens; Area; Award; Benign; Biological Assay; Biology; Biometry; Blood Coagulation Disorders; Carrier State; Categories; Cell Culture System; Cell Line; Cells; Chromogenic Substrates; Classification; Clinical; Clinical Management; Coagulation Process; Complement; Cultured Cells; Data; Desmopressin; Development; Diagnostic; Endothelial Cells; Ensure; Evaluation; Event; Experimental Designs; F8 gene; Factor V; Factor VIII; Feedback; Female; Future; Generations; Goals; Health; Hematology; Hemophilia A; Hemorrhage; Hemostatic Agents; Hemostatic function; Impairment; Individual; Injury; Investigation; K-Series Research Career Programs; Life; Link; Logistic Regressions; Measures; Mentors; Mentorship; Methods; Modeling; Molecular; Mosaicism; Mutation; Operative Surgical Procedures; Outcome; Pathway interactions; Pattern; Perinatal; Phenotype; Physiological; Plasma; Population; Postpartum Hemorrhage; Postpartum Period; Pregnancy; Process; Recording of previous events; Research; Resistance; Risk; Role; Sampling; Scientist; Symptoms; TFPI; Testing; Thrombin; Training; Training Programs; Validation; Woman; Work; X Chromosome; X Inactivation; activated Protein C; adverse outcome; biological adaptation to stress; career; career development; clinically relevant; clinically significant; cohort; experience; genetic variant; high risk; improved; improved outcome; innovation; male; meetings; men; multidisciplinary; mutant; novel strategies; programs; prospective; response; risk prediction; risk prediction model; risk stratification; stressor; success; translational research program; treatment response

Project Summary/Abstract This K08 Mentored Clinical Scientist Research Career Development Award application details a 5-year training program to advance Dr. Cygan’s career goal of developing an independent research program in hemostasis focused on bleeding tendency in female Hemophilia A carriers. The scientific proposal seeks to investigate bleeding tendency in Hemophilia A (HA) carriers, which remains largely underrecognized and poorly understood. HA is due to mutations within the F8 gene encoding coagulation Factor VIII (FVIII), and is commonly thought to affect only men, while female HA carriers are thought to be only rarely symptomatic. There are an estimated four female HA carriers for every one HA male, and increasing evidence indicates that decreased FVIII levels and bleeding symptoms in HA carriers are not rare. Many have significant bleeding events despite Factor VIII activity levels considered adequate in males. Current understanding of bleeding tendency in this area is lacking, and research investigating female HA carriers would greatly inform their classification and management. The proposal seeks to develop a risk prediction model for bleeding tendency in HA carriers, using parameters other than standard coagulation testing. In Aim 1, a multivariable risk prediction model will be developed and validated. In Aim 2, a cell culture system to model the HA carrier state will be developed and the role of X-chromosome inactivation (XCI) in altering basal and stimulated levels of FVIII and resulting thrombin generation will be evaluated. In Aim 3, the role that natural anticoagulants alter hemostasis and explain differences in bleeding phenotypes between HA carriers independent of XCI will be investigated. During the award period, Dr. Cygan will continue to develop his expertise in benign hematology, and further expand his abilities in experimental design and implementation. A multidisciplinary mentorship team has been assembled to ensure the success of this project and includes expertise in X chromosome biology, Factor VIII expression, clinical hematology and biostatistics. The mentorship team includes Dr. Laura Carrel, Dr. Valder R. Arruda and Dr. M. Elaine Eyster; they will guide Dr. Cygan in meeting his training objectives through direct research experience, formal didactics, participation in institutional seminars and junior career development opportunities. Dr. Lan Kong, a biostatistician, will contribute to Dr. Cygan’s research and career plan as a collaborator and statistical advisor.

项目摘要/摘要 这款K08指导的临床科学家研究职业发展奖应用程序详细介绍了5年的培训 促进Cygan博士的职业目标的计划，以制定止血性独立研究计划 专注于雌性血友病A携带者的出血趋势。科学提议旨在调查 血友病A（HA）载体的出血趋势，在很大程度上被识别且较差 理解齿。 HA是由于编码凝结因子VIII（FVIII）的F8基因内的突变所致，并且为 通常认为只会影响男性，而女性HA载体则被认为很少有症状。 估计每一个HA男性有四个女性HA载体，越来越多的证据表明 HA携带者的FVIII水平降低和出血症状并不罕见。许多人出血很大 事件目标因子VIII活性水平在男性中被认为是足够的。当前对出血的理解 缺乏该领域的趋势，调查女性HA载体的研究将大大告知他们 分类和管理。该提案旨在为出血趋势开发风险预测模型 HA载体，使用标准凝结测试以外的其他参数。在AIM 1中，多变量风险预测 模型将被开发和验证。在AIM 2中，将建模HA载体状态的细胞培养系统将是 开发以及X染色体灭活（XCI）在改变基本和刺激水平的FVIII和 将评估产生的凝血酶生成。在AIM 3中，天然抗凝剂改变止血的作用 并解释将研究独立于XCI的HA载体之间出血表型的差异。 在奖励期间，Cygan博士将继续发展他在良性血液学方面的专业知识，并进一步发展 扩大他在实验设计和实施方面的能力。一个多学科的概括团队已经 组装以确保该项目的成功，并包括X染色体生物学方面的专业知识 表达，临床血液学和生物统计学。心态小组包括Laura Carrel博士，Valder R.博士。 Arruda和M. Elaine Eyester博士；他们将指导Cygan博士通过直接达到他的培训目标 研究经验，形式教学，参与机构半货和初级职业发展 机会。生物统计学家Lan Kong博士将为Cygan博士的研究和职业计划做出贡献 合作者和统计顾问。