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: 10283380
• 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/10283380
• 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.

项目概要/摘要 此 K08 指导临床科学家研究职业发展奖申请详细介绍了 5 年培训 旨在推进 Cygan 博士开发独立止血研究项目的职业目标的计划 重点关注女性甲型血友病携带者的出血倾向。该科学提案旨在调查 A 型血友病 (HA) 携带者的出血倾向，但在很大程度上仍未得到充分认识和认识不足 明白了。 HA 是由于编码凝血因子 VIII (FVIII) 的 F8 基因内的突变引起的，并且是 通常认为仅影响男性，而女性 HA 携带者被认为很少出现症状。 据估计，每 1 名 HA 男性携带者就有 4 名女性 HA 携带者，并且越来越多的证据表明 HA 携带者中 FVIII 水平下降和出血症状并不罕见。许多人有严重出血 尽管第八因子活性水平在男性中被认为是足够的，但仍然发生了这些事件。目前对出血的认识 该领域缺乏趋势，调查女性 HA 携带者的研究将极大地告知他们 分类管理。该提案旨在开发一种出血倾向的风险预测模型 HA 载体，使用标准凝血测试以外的参数。在目标 1 中，多变量风险预测 将开发并验证模型。在目标 2 中，将建立一个模拟 HA 载体状态的细胞培养系统 X 染色体失活 (XCI) 在改变 FVIII 和刺激水平的基础和刺激水平中的作用 将评估由此产生的凝血酶。在目标 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 携带者之间出血表型的差异。 在获奖期间，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 扩展他在实验设计和实施方面的能力。一支多学科的导师团队 聚集以确保该项目的成功，并包括 X 染色体生物学、因子 VIII 方面的专业知识 表达、临床血液学和生物统计学。导师团队包括 Laura Carrel 博士、Valder R. Arruda 和 M. Elaine Eyster 博士；他们将通过直接指导 Cygan 博士实现他的培训目标 研究经验、正式教学、参加机构研讨会和初级职业发展 机会。生物统计学家 Lan Kong 博士将作为 Cygan 博士的研究和职业规划的贡献者 合作者和统计顾问。