Analysis and Characterization of Trauma-Induced Coagulopathy

描述(申请人提供)：失控出血是暴露在严重创伤中的成年人死亡的主要原因。创伤性凝血障碍(TIC)发生在损伤和休克后，伴随着炎症和凝血事件的“风暴”，导致止血过程丧失能力。TICS损害止血系统，因为在全身性的基础上发生的失调过程中，蛋白质分解系统破坏基本的凝血成分。以往的研究已经证实激活的蛋白C介导了辅因子Va的破坏，并涉及到全身纤溶活性，其中无调控的蛋白分解破坏了纤维蛋白原和部分血浆凝血系统。在TIC患者的静脉采血中观察到的这些终末事件是由血液和血管组织中的蛋白质、细胞和细胞因子以及组织损伤物质进入血液的体内过程引起的。抽搐的原因和广度尚不清楚。这一策略建议全面评估血浆蛋白、血细胞、血管内皮细胞、血管和血管外组织对TIC的贡献，利用独特的基础设施，其中包括参与创伤试验和系统生物学的已获得资金的国防部地点。由凝血和炎症研究领域的主要研究人员组成的一个全面的团队方法，使用体外和体内方法的组合来解决这个问题，以确定导致抽搐的候选人。早期将实验室结果转化为有用的技术将由一套5个战术创伤中心实现。在这些研究的同时，将发展与参与国防部临床试验的临床中心的互动，每个中心的研究人员将负责护理点研究和血液样本的处理。收集技术将利用抑制性鸡尾酒来阻止体外、静脉切开后的人工制品。血液/血浆样本将被运往安全的储存库，并利用新技术进行分析，以确定TIC事件的自然历史。TRACT研究项目的继续将取决于它们对创伤患者的诊断和治疗选择的潜在效用。虽然失控出血是严重创伤患者死亡的主要原因，但出血的原因尚不完全清楚。我们计划全面描述与创伤相关的凝血和出血的原因，并提出诊断不同原因的方法，并最终提出治疗干预措施，以防止创伤环境中的发病率和死亡率。

DESCRIPTION (provided by applicant): Uncontrolled hemorrhage is the major cause of death in adults exposed to severe trauma. Trauma induced coagulopathy (TIC) occurs after injury and shock, accompanied by a "storm" of inflammatory and coagulation events leading to incapacitation of the hemostatic process. TICs compromise the hemostatic system because of dysregulated processes occurring on a systemic basis in which proteolytic systems destroy essential coagulation components. Previous studies have identified activated protein C-mediated destruction of the cofactor factor Va and implicated systemic fibrinolytic activity in which unregulated proteolysis destroys fibrinogen and parts of the plasma coagulation system. These terminal events observed in phlebotomy blood of TIC patients are caused by in vivo processes involving the proteins, cells and cytokines in blood and vascular tissues and tissue damage material entering the blood. The causes and breadth of TICs are not understood. This TACTIC proposal provides a comprehensive evaluation of the contributions of plasma proteins, blood cells, the vascular endothelium, the blood vessel, and extravascular tissue to TIC, making use of a unique infrastructure that includes already-funded DoD sites involved in trauma trials and Systems Biology. A comprehensive team approach by leading investigators in coagulation and inflammation research addresses the problem using a composite of in vitro and in vivo approaches to identify candidates responsible for TICs. Early translation of laboratory results into useful technology will be enabled by a set of 5 TACTIC trauma centers. Simultaneous with these studies, interactions with clinical centers engaged in DoD clinical trials will be developed in which research personnel at each center will be responsible for point-of-care studies and processing of blood samples. Collection techniques will utilize inhibitory cocktails to block ex vivo, post phlebotomy artifacts. Blood/plasma samples will be shipped to a secure repository and analyzed utilizing new technology to identify the natural history of TIC events. Continuation of TACTIC research projects will be dependent upon their potential utility for diagnosis and selection of therapy for trauma patients. Although uncontrolled bleeding is the major cause of death in people with severe traumatic injuries, the reasons for this bleeding are not completely understood. We plan to comprehensively describe the causes of trauma-related clotting and bleeding, and propose methods to diagnose the different causes and ultimately therapeutic interventions to prevent morbidity and mortality in traumatic settings.