Endothelial Dysfunction and Restoration in Trauma Induced Coagulopathy

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.