Endothelial Dysfunction and Restoration in Trauma Induced Coagulopathy

项目摘要/摘要： 创伤引起的凝血障碍(TIC)是严重创伤后发病率和死亡率的主要驱动因素。 影响多达30%的危重创伤患者，TIC代表了一系列凝血表型。 从早期止血受损到后来的微血管和大血管血栓并发症。我们有 确定TIC患者有严重内皮损伤的证据，而这些内皮细胞标志物 创伤与创伤的结局密切相关。此外，通过随机对照试验测试预 医院血浆作为复苏工具，我们已经确认血浆输注可以减少内皮细胞 受伤，即使在受伤程度最高的患者中也是如此。血浆输注可降低重症后的死亡率 创伤，但受益的确切机制尚不清楚。在本提案中，我们针对中央 假设内皮细胞是TIC的中枢调节因子。我们建议将其角色定性为 内皮作为不良适应反应的调节器和血栓形成-炎症的关键界面 相声。我们的战略将专注于确定创伤后诱导内皮细胞生长的关键循环介质 受伤。我们将利用一个“提示、信号、反应”的框架来有力地描述分子途径。 血管内皮细胞的激活以及血管内皮细胞的反应如何与凝血功能的变化相联系 回应。最后，我们将定义血浆输注所产生的“修复表型”，恢复 内皮细胞向动态平衡转变。我们将利用这一点来测试有针对性的治疗，以解决创伤中未得到满足的需求 以内皮健康为目标的复苏。这种方法将利用最新的科学和小说 蛋白质组学、转录组学、代谢组学、先进的微血管成像和临床前技术 除了以前收集的大量创伤患者外，还包括创伤和出血的模型 样本。

Project summary/abstract: Trauma-induced coagulopathy (TIC) is a leading driver of morbidity and mortality following severe injury. Affecting as many as 30% of critically ill trauma patients, TIC represents a spectrum of coagulation phenotypes ranging from early impaired hemostasis to later micro and macrovascular thrombotic complications. We have identified that patients with TIC have evidence of severe endothelial damage, and these markers of endothelial injury correlate closely with outcomes in trauma. Further, through randomized controlled trials testing pre- hospital plasma as a resuscitation tool, we have identified that plasma transfusion can reduce endothelial injury, even in the patients with the highest injury severity. Plasma transfusion reduces mortality after severe trauma, but the exact mechanism of benefit is unknown. In the present proposal, we address the central hypothesis that the endothelium is a central regulator of TIC. We propose to characterize the role of the endothelium as the regulator of maladaptive response and a crucial interface for thrombosis-inflammation crosstalk. Our strategy will focus on identifying key circulating mediators after trauma that induce endothelial injury. We will utilize a “cue, signal, response” framework to robustly characterize the molecular pathways activated in the endothelial and how the endothelial response interfaces with changes in the coagulation response. Finally, we will define the “reparative phenotype” that plasma transfusion creates, restoring the endothelium to homeostasis. We will use this to test targeted therapies to address the unmet needs in trauma resuscitation targeting endothelial health. The approach will leverage state-of-the-science and novel techniques in proteomics, transcriptomics, metabolomics, advanced microvascular imaging, and pre-clinical models of trauma and hemorrhage in addition to a large repository of previously collected trauma patient samples.