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.

怀孕呈现出一种血液学悖论。尽管出血是产妇死亡的主要原因 在世界范围内，怀孕是一种众所周知的过度凝结状态，导致临床发病率显著增加。 妊娠和产褥期观察到的血栓栓塞性事件。这种高凝状态就会出现 与性激素水平的增加有关。然而，绝大多数孕妇(99.9%)没有 妊娠期或产后期的血栓事件，尽管出血并发症和 大约10%的妇女存在先兆子痫(及其相关的血液系统疾病)。此外，在 接受药物促排卵的妇女妊娠早期血栓形成风险增加 到10倍，但在这里，绝大多数(99.6%)保持适当的止血平衡，并保持无 临床并发症。在这项提案中，我们将确定补偿机制，以提供保护 并建立数学模型，将这些机械性的见解与个人的具体情况相结合 临床参数和选择生物标记物的值来预测妊娠期间异常止血的风险。R61： 确定并定量评估可预防血栓形成事件的适当止血途径 以及药物诱导排卵和围产期事件如何影响这些途径。我们会收集 建立与怀孕期间性激素影响相关的自然病史的数据。在一个队列中，协助 自然怀孕将从怀孕前到怀孕前三个月进行纵向评估，而在另一个月则进行纵向评估 队列中，妊娠将从妊娠晚期持续到产后几个月比较剖宫产 阴道分娩有分娩和无分娩两种情况。数据将包括临床和人体测量参数， 动态评估止血平衡(血栓稳定性)，生物标记物测量捕捉变化 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、抗凝剂和 每个个体的纤溶蛋白质组将提供对所观察到的止血变化的机械性见解 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，既确定了预防血栓形成的机制，又预测了 最常见的临床问题，包括助孕期间植入失败和出血 在分娩过程中；2)启动一项关于助孕和自然妊娠的纵向研究，其中每个人 从孕前到产后使用动态和静态分析(从R61期开始) 表现出对性激素浓度变化最敏感；3)成熟并初步验证 模型采用纵向研究数据。评估个体特异性止血曲线的预测模型 将推进监测怀孕和评估风险的新方法，以增加对 治疗性干预。