TFPI, Protein S, and Plasma FIXa in Hormone-Induced Hypercoagulability

TFPI、蛋白 S 和血浆 FIXa 在激素诱导的高凝状态中的作用

• 批准号: 10452480
• 负责人: Alan E Mast
• 金额: $ 72.12万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452480
• 关键词: Anticoagulants; Antithrombins; Binding; Biochemical; Biochemical Genetics; Biochemical Markers; Biochemistry; Biological Assay; Biological Markers; Blood Coagulation Factor; Blood coagulation; Blood donor; Blood specimen; Clinical; Clinical Research; Coagulation Process; Contraceptive Usage; Custom; Data; Decision Making; Disease; Estrogens; Event; Exhibits; Factor IXa; Female; Female Adolescents; Gene Chips; Generations; Genes; Genetic; Genetic Markers; Genetic Risk; Goals; Hemostatic Agents; High Risk Woman; Hormones; Human; Hyperactivity; Individual; Injections; Liver; Longitudinal cohort; Measurement; Measures; Mediating; Menorrhagia; Modeling; Mus; Oral Contraceptives; Pathway interactions; Plasma; Plasma Proteins; Polycystic Ovary Syndrome; Predictive Value; Predisposition; Premenopause; Production; Protein S; Proteins; Questionnaires; Recombinants; Recording of previous events; Resistance; Risk; Role; Sampling; Severities; Signal Transduction; System; TFPI; Techniques; Thrombin; Thrombophilia; Thrombosis; Thrombus; Time; United States; Variant; Withdrawal; Woman; activity marker; age group; base; clinically significant; cohort; density; endometriosis; evidence base; experimental study; factor V Leiden; genetic risk factor; genetic variant; genome wide association study; high risk; hormone therapy; innovation; non-genetic; prospective; response; trait; venous thromboembolism; young woman

Venous thromboembolism (VTE) in women taking oral contraceptives (OC) is a problem of broad clinical significance that is mediated, at least in part, by estrogen effects on the expression of blood coagulation proteins by the liver or vasculature. Our overall goal is to identify and characterize the underlying coagulation pathways leading to OC-induced hypercoagulability and to identify genetic factors prevalent in individuals at highest risk for VTE. OC use decreases the plasma concentration of two endogenous anticoagulant proteins, tissue factor pathway inhibitor (TFPI) and protein S (PS) that modulate plasma FIXa production and activity. We have developed a highly sensitive and specific (<10 pmol/L) technique for measurement of plasma FIXa activity using an enhanced thrombin generation assay, which amplifies the FIXa signal from subject plasma via thrombin generation in FIX-deficient plasma. Using this assay in plasma samples from blood donors we found that OC-induced changes in TFPI and PS are associated with elevated plasma factor IXa (FIXa) activity in ~30% of women taking OC. Our central hypothesis is that OC use alters the inhibition of procoagulant responses by the natural anticoagulants TFPI and PS, producing large increases in plasma factor IXa (FIXa) activity and a systemic hypercoagulable state. This hypothesis will be probed to identify biochemical and genetic correlates of OC-induced hypercoagulability. Biochemical studies using recombinant FIX variants resistant to antithrombin or PS binding will be used to define how TFPI and PS modulate FIXa generation in human plasma-based systems. The clinical impact of the biochemical findings will be examined by measurement of plasma levels of TFPI, PS, and FIXa, GWAS analysis, and a thrombosis history questionnaire in two cohorts of pre-menopausal women: 1) a cross-sectional cohort of ~1000 pre-menopausal blood donors; and 2) a longitudinal cohort of ~45 adolescent girls to be followed for one year after initiation of OC-therapy. The data collected in the cross-sectional cohort will be modeled to identify non-genetic and genetic factors that correlate with OC-associated differences in plasma TFPI, PS and FIXa and thrombosis history. The data collected in the longitudinal cohort will be used to examine the time course and stability of the OC-induced plasma hypercoagulable state within individuals using repeated measures analysis. These findings will be used to validate plasma protein changes and the effect of SNPs identified by GWAS in the cross-sectional cohorts. The proposed experiments will define the biochemical and genetic underpinnings of the OC-induced hyper- coaguable state focused on our finding of elevated amounts of an activated clotting factor, FIXa, in the plasma of about 30% of women using OC. These results will also establish rationale for further clinical studies to define the predictive value of plasma FIXa and associated genetic markers for OC-induced thrombosis and facilitate evidence-based decision-making for women considering use of OC and related hormonal therapies.

服用口服避孕药（OC）的女性静脉血栓栓塞（VTE）是广泛临床的问题 雌激素对血液凝结表达的影响至少部分地介导了意义 肝脏或脉管系统的蛋白质。我们的总体目标是识别和表征潜在的凝结 导致OC诱导的高凝性的途径，并确定个体普遍存在的遗传因素 VTE的最高风险。 OC使用降低了两个内源性抗凝蛋白的血浆浓度， 组织因子途径抑制剂（TFPI）和蛋白S（PS）调节血浆固定的产生和活性。 我们已经开发了一种高度敏感和特异性（<10 pmol/L）的技术，用于测量血浆fixa 使用增强的凝血酶生成测定的活动，该测定法可以通过受试者血浆的FIXA信号通过 固定缺陷等离子体中的凝血酶生成。在我们发现的血浆样品中使用此测定 OC诱导的TFPI和PS的变化与血浆IXA（FIXA）活性升高有关 约有30％的女性服用OC。我们的中心假设是OC使用会改变抑制procagulant 天然抗凝剂TFPI和PS的反应，血浆IXA（FIXA）的大幅增加 活动和全身性高凝状态。该假设将被探讨以识别生化和 OC诱导的高凝性的遗传相关性。使用重组固定变体的生化研究 对抗凝血酶或PS结合的耐药性将用于定义TFPI和PS如何调节FIXA的生成 基于人血浆的系统。生化发现的临床影响将由 TFPI，PS和FIXA，GWAS分析和血栓形成历史问卷的血浆水平的测量 在两名冠军前妇女中：1）约有1000个绝经前献血者的横截面队列； 2）在开始OC-疗法后一年，纵向一年的纵向队列将跟随约45名青春期女孩。 将对横截面队列中收集的数据进行建模，以识别非遗传和遗传因素 与血浆TFPI，PS和FIXA和血栓形成史的OC相关差异相关。数据 在纵向队列中收集的将用于检查OC诱导的时间过程和稳定性 使用重复测量分析的个体内血浆高凝状态。这些发现将被使用 为了验证血浆蛋白变化以及GWAS在横截面队列中鉴定出的SNP的作用。 所提出的实验将定义OC诱导的超级化学的生化和遗传基础 可辅助状态的重点是我们在等离子体中发现的激活凝结因子fixa的发现 大约30％的使用OC的妇女。这些结果还将为进一步的临床研究建立基本原理以定义 血浆固定的预测值和相关的OC诱导血栓形成的遗传标记和促进 考虑使用OC和相关激素疗法的妇女循证决策。