The interaction of basal risk, pharmacologic ovulation induction, pregnancy and delivery on hemostatic balance

基础风险、药物促排卵、妊娠和分娩对止血平衡的相互作用

• 批准号: 10026344
• 负责人: IRA MARK BERNSTEIN
• 金额: $ 75.8万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026344
• 关键词: Affect; Algorithms; Anticoagulants; Base Composition; Behavior; Biochemical; Biological Assay; Biological Markers; Blood coagulation; Cesarean section; Clinical; Clinical Data; Coagulants; Coagulation Process; Computer Models; Conceptions; Data; Diagnostic; Drops; Equilibrium; Estradiol; Event; F8 gene; Failure; Fibrin; Fibrinogen; Fibrinolysis; First Pregnancy Trimester; Generations; Gonadal Steroid Hormones; Hematological Disease; Hematology; Hemorrhage; Hemostatic Agents; Hemostatic function; Hormones; Implant; Individual; Laboratory Markers; Link; Longitudinal Studies; Maternal Mortality; Measurement; Measures; Modeling; Monitor; Natural History; Normal Range; Ovulation Induction; Pathway interactions; Patients; Perinatal; Pharmacology; Phase; Phenotype; Plasma; Polycystic Ovary Syndrome; Population; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnant Women; Process; Proteome; Puerperium; Risk; Route; Serum; Therapeutic Intervention; Third Pregnancy Trimester; Thrombin; Thrombophilia; Thrombosis; Thrombus; Vagina; Vaginal delivery procedure; Variant; Woman; Work; base; clinical practice; cohort; idiopathic infertility; implantation; improved; inflammatory marker; insight; male; mathematical model; novel strategies; predictive modeling; prepregnancy; steroid hormone; thrombogenesis; tool

Pregnancy presents a hematologic paradox. Despite hemorrhage being the leading cause of maternal mortality worldwide, pregnancy is a well described hypercoaguable state, conferring a significant increase in clinical thromboembolic events observed during pregnancy and the puerperium. This hypercoagulable state appears linked to increases in sex hormone levels. However, the vast majority of pregnant women (99.9%) do not have a thrombotic event during pregnancy or the post-partum period, although bleeding complications and preeclampsia (with its associated hematologic disorders) exist in approximately 10% of women. Additionally, in women undergoing pharmacologic ovulation induction the risk of thrombosis in the first trimester is increased up to 10-fold, but here too the vast majority (99.6%) maintain an appropriate hemostatic balance and remain free of clinical complications. In this proposal, we will identify compensating mechanisms that confer protection from thrombosis and build mathematical models that combine these mechanistic insights with an individual's specific clinical parameters and select biomarker values to predict risk for aberrant hemostasis across pregnancy. R61: Identify and quantitatively assess the hemostatic pathways in place that may protect against thrombotic events and how pharmacologic ovulation induction and peripartum events may affect these pathways. We will collect data to establish a natural history relevant to sex hormone influence during pregnancy. In one cohort, assisted and natural pregnancy will be longitudinally assessed from pre-pregnancy to the first trimester while in the other cohort, pregnancy will be followed from the 3rd trimester to several months postpartum comparing cesarean delivery with and without labor with vaginal delivery. Data will include clinical and anthropometric parameters, dynamic assessments of hemostatic balance (thrombus stability), biomarker measurements capturing alterations in pre-pregnancy coagulant/anticoagulant/fibrinolytic components and pathways, and markers of inflammation and cellular activation. Computational modeling assessing the contributions of the coagulant, anticoagulant and fibrinolytic proteome of each individual will provide mechanistic insights into observed alterations in hemostatic balance. R33: 1) Develop models that integrate clinical data, dynamic measures and biomarker data from the R61 phase to both identify mechanisms that confer protection from thrombosis and to predict individual risk for the most common clinical problems, including failure to implant during assisted pregnancy and hemorrhage during delivery; 2) Initiate a longitudinal study of assisted and natural pregnancy in which each individual is followed from pre-pregnancy into the postpartum period using dynamic and static assays (from R61 phase) that appeared most responsive to the changes in sex hormone concentrations; 3) Mature and validate the preliminary models using the longitudinal study data. Predictive models that evaluate individual-specific hemostatic profiles will be advanced to novel approaches of monitoring pregnancy and evaluating risk to enhance opprtunity for therapeutic interventions.

怀孕呈现出血液学悖论。尽管出血是孕产妇死亡的主要原因 在世界范围内，妊娠是一种充分描述的高凝状态，导致临床上的高凝状态显着增加。 妊娠期和产褥期观察到的血栓栓塞事件。这种高凝状态出现 与性激素水平的增加有关。然而，绝大多数孕妇（99.9%）没有 妊娠期间或产后期间的血栓事件，尽管出血并发症和 大约 10% 的女性患有先兆子痫（及其相关的血液系统疾病）。另外，在 接受药物促排卵的女性在妊娠早期血栓形成的风险会增加 至 10 倍，但这里绝大多数人 (99.6%) 也保持适当的止血平衡，并且没有 临床并发症。在本提案中，我们将确定补偿机制，以提供保护 血栓形成并建立数学模型，将这些机制见解与个人的具体情况相结合 临床参数并选择生物标志物值来预测整个怀孕期间异常止血的风险。 R61： 识别并定量评估可预防血栓事件的止血途径 以及药物促排卵和围产期事件如何影响这些途径。我们将收集 建立与怀孕期间性激素影响相关的自然史的数据。在一组中，协助 自然妊娠将从怀孕前到妊娠早期进行纵向评估，而在其他情况下 队列中，与剖宫产相比，妊娠将从妊娠第三个月到产后几个月进行跟踪 阴道分娩和非分娩分娩。数据将包括临床和人体测量参数， 止血平衡（血栓稳定性）的动态评估、捕捉变化的生物标志物测量 孕前凝血/抗凝/纤溶成分和途径以及炎症标志物 和细胞激活。评估凝血剂、抗凝血剂和凝血剂的贡献的计算模型 每个人的纤溶蛋白质组将为观察到的止血变化提供机制见解 平衡。 R33：1）开发集成临床数据、动态测量和生物标志物数据的模型 R61 阶段既可以识别防止血栓形成的机制，又可以预测个体的风险 最常见的临床问题，包括辅助妊娠期间植入失败和出血 交货期间； 2) 启动一项辅助妊娠和自然妊娠的纵向研究，其中每个人都 使用动态和静态分析（从 R61 阶段）跟踪从怀孕前到产后期的情况 似乎对性激素浓度的变化最敏感； 3）初步成熟并验证 使用纵向研究数据的模型。评估个体特异性止血曲线的预测模型 将推进监测妊娠和评估风险的新方法，以增加怀孕机会 治疗干预。