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

基本信息

批准号：
10676788
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
项目类别：
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/10676788
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 Institution 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 statistics stressor success translational research program treatment response

项目摘要

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该科学提案旨在调查女性 A 型血友病携带者的出血倾向。 A 型血友病 (HA) 携带者的出血倾向，在很大程度上仍未得到充分认识和认识不足据了解，HA 是由编码凝血因子 VIII (FVIII) 的 F8 基因内的突变引起的。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，每一位 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，许多人出现严重出血。尽管目前对男性出血的理解是足够的，但因子 VIII 的活性水平仍然存在。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该提案旨在开发出血倾向的风险预测模型。 HA 携带者，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，将建立一个细胞培养系统来模拟 HA 载体状态。 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在目标 3 中，将评估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，并进一步扩大了他在实验设计和实施方面的能力。聚集以确保该项目的成功，并包括 X 染色体生物学、因子 VIII 方面的专业知识导师团队包括 Laura Carrel 博士、Valder R. 博士。 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生物统计学家 Lan Kong 博士将作为 Cygan 博士的研究和职业计划的贡献者。合作者和统计顾问。