OPTIMUM OB-TXA: Optimal TIMing, route and dose of tranexamic acid prior to UMbilical cord clamp for postpartum hemorrhage prevention

项目摘要 该提案的主要目标是填补与氨甲环酸（TXA）的时间，途径和剂量相关的关键空白 在预防产后出血（PPH）中，最大限度地提高产妇获益，同时最大限度地减少胎儿-新生儿和 产妇风险以我在母胎医学的临床背景，流行病学的研究经验， 和翻译凝固方法，并事先初步数据，我有专业知识和较强的科学性 成功实现这些目标的前提。创新研究的重点是三个独特的 亚群（阴道分娩、剖宫产、病态肥胖），并有三种TXA给药途径 （静脉注射2分钟以上，静脉注射10分钟以上和肌肉注射）。 新生儿暴露也将通过脐带血和母乳中的TXA浓度进行评估， 作为分娩时、产后2周和6周的临床结局。具体目标如下：1a） 确定预防性TXA预防PPH的最佳时机、途径和剂量1b）确定新生儿 在脐带钳夹前给予TXA时，通过经胎盘转移和母乳暴露于TXA，以及 2)表征TXA后母体循环中的血栓前和纤溶生物标志物。创新 这项赠款的性质是多方面的：a）重新利用一种廉价的非专利药品，以解决产科 出血; B）探索通过IM和2分钟输注快速给药，以改善低资源的可及性 c）脐带钳夹前TXA给药作为一种新的方法，尚未在大型产科临床试验中考虑 试验; d）在独特亚群（病态肥胖，阴道分娩）中的剂量优化; e）生物标志物安全性 f）一个强有力的多学科专家小组， 专业知识具体来说，团队成员在临床药理学、新生儿医学、实验室医学、 血栓形成和止血，孕妇和新生儿的临床试验，药物计量学和 流行病学/生物统计学。我有一个理想的工作环境，植根于临床和转化科学 研究所与GW和儿童国立医院合作，但也通过补充地点进行了扩展， 马里兰州大学转化医学中心和北卡罗来纳州大学凝血实验室。在 总之，这一建议提出的目标是重要的，创新的，可行的，并将有助于产科 社区更好地了解如何使用TXA优化围产期止血，同时确保 最大限度地降低胎儿/新生儿风险。最终，我们的工作将回答作为解决方案一部分的重要问题 如何预防孕产妇发病率和死亡率， 年

Project Summary The primary goal of this proposal is to fill critical gaps related to timing, route and dose of tranexamic acid (TXA) in prevention of postpartum hemorrhage (PPH) to maximize maternal benefit while minimizing fetal-neonatal and maternal risks. With my clinical background in Maternal-Fetal Medicine, research experiences in epidemiologic and translational coagulation methods, and prior preliminary data, I have the expertise and strong scientific premise to successfully complete these aims. The proposed innovative study focuses on three unique subpopulations (vaginal delivery, cesarean delivery, morbid obesity) and has three routes of TXA administration (intravenous over 2 minutes, intravenous over 10 minutes and intramuscular) immediately prior to childbirth. Neonatal exposure will be assessed through TXA concentrations in umbilical cord blood and breast milk, as well as clinical outcomes at delivery, 2 weeks and 6 weeks postpartum. The specific aims are as follows: 1a) Determine the optimal timing, route and dose of prophylactic TXA for prevention of PPH 1b) Determine neonatal exposure to TXA through transplacental transfer and breast milk when TXA is administered pre-cord clamp, and 2) Characterize prothrombotic and fibrinolytic biomarkers in maternal circulation following TXA. The innovative nature of this grant is multifold: a) repurposing an inexpensive generic drug to address disparities in obstetric hemorrhage; b) exploring rapid administration via IM and 2min infusion to improve access in low resource settings; c) pre-cord clamp TXA administration as a novel approach not yet considered in large obstetric clinical trials; d) refinement of dosing in unique subpopulations (morbidly obese, vaginal delivery); e) biomarker safety including a no drug group and f) a robust team of multidisciplinary experts with regional and international expertise. Specifically, team members have expertise in clinical pharmacology, neonatal medicine, lab medicine, thrombosis and hemostasis, clinical trials in pregnant women and newborns, pharmacometrics and epidemiology/biostatistics. I have an ideal working environment, rooted in the Clinical and Translational Science Institute partnering GW and Children’s National Hospital but also extended through supplemental sites at University of Maryland Center for Translational Medicine and University of North Carolina Coagulation Lab. In summary, this proposal sets forth aims that are significant, innovative, feasible, and will help the obstetric community better understand how peripartum hemostasis can be optimized using TXA while being sure to minimize fetal/neonatal risks. Ultimately, our work will answer important questions that are part of the solution for how to prevent maternal morbidity and mortality for the 140 million women worldwide that give birth each year.