Mechanism of Traumatic Coagulopathy

创伤性凝血病的机制

基本信息

批准号：
8318769
负责人：
Mitchell Cohen
金额：
$ 11.88万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-18 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8318769
关键词：
AIDS/HIV problem Accident and Emergency department Acidosis Acute Affect Applications Grants Basic Science Blocking Antibodies Blood Coagulation Disorders Blood Coagulation Factor Cause of Death Cell membrane Cell surface Characteristics Clinical Sciences Coagulation Process Complement Complement Activation Complex Computer Simulation Conceptions Consumption Data Development Elements Endothelial Cells Experimental Models Fibrin Fibrinolysis Fluid Therapy Generations Grant Graph Hemorrhage Human IV Fluid Imagery In Vitro Inflammation Inflammation Mediators Injury Investigation Ischemia Laws Link Liquid substance Mediating Modeling Molecular Morbidity - disease rate Mus Myocardial Ischemia Organ Outcome Output Pathway interactions Patients Protein C Protein Inhibition Reperfusion Therapy Reporting Research Personnel Resuscitation Role Shock Social Sciences Stroke Structure System Systems Biology Techniques Testing Therapeutic Thrombomodulin Thrombosis Time Tissues Trauma Vascular Endothelium activated Protein C base biological systems citrate carrier clinically significant complement pathway derepression disability in vitro Model in vivo injury burden interest mortality mouse model programs protein activation research study theories tool

项目摘要

DESCRIPTION (provided by applicant): The applicant will test in this grant the hypothesis that acute traumatic coagulopahty is primarily caused by tissue hypoperfusion resulting in a complement mediated activation and subsequent depletion of the protein C pathway (AIMS 1 and 2). While the in vitro and in vivo approaches detailed in AIMS 1 and 2 will provide important mechanistic information regarding acute traumatic coagulopathy, the coagulation system is of such complexity to be completely visualized using the traditional cascade. The applicant will test the hypothesis that new techniques in network topology and dynamic modeling will allow for superior visualization and predict changes in the structure and function of the protein C system after trauma (AIM 3). Specifically he will first use a mouse model of trauma/shock to determine the timing and mechanism of perturbations in protein C after trauma and hypoperfusion. Secondly, he will use both the in vivo mouse model as well as an in vitro model of endothelial cell ischemia reperfusion to test the role of complement in activation of protein C after trauma and shock. Third, he will utilize a network representation of the protein C pathway as well as a newly constructed dynamic model of protein C to model in silico the protein C pathway after trauma and shock. The information obtained in these experiments will have important therapeutic significance in humans. The preliminary data from trauma patients that form the rationale for this grant application indicates that coagulation and complement abnormalities begin early after trauma, and are associated with significant morbidity and increased mortality. Thus understanding the molecular and systems level mechanisms associated with post traumatic coagulation and complement abnormalities may provide new avenues for therapy in trauma patients. The concerns here are that the model does replicate elements of what patients present with clinically. The typical trauma patient has not suffered only a loss on intravascular volume but has associated tissue injury. Damaged tissue represents an important part of the injury burden and contributes to the post injury dyshomeostasis. How this will impact the interpretation of the experimental model output needs to be directly considered by the applicant. Aim 3 entails dynamic modeling based on the results of Aim 1 and 2 data and as such is an interesting approach. The question is how will it be validated as reflective of what occurs in trauma patients?

描述（由申请人提供）：申请人将在本赠款中检验以下假设：急性创伤性凝结蛋白凝血石主要是由组织灌注不足引起的，从而导致补体介导的激活和随后的蛋白质C途径的耗竭（AIMS 1和2）。虽然Aim 1和2中详细介绍的体外和体内方法将提供有关急性创伤性凝血病的重要机械信息，但使用传统级联反应完全可视化凝血系统是如此复杂。申请人将检验以下假设：网络拓扑和动态建模中的新技术将使创伤后蛋白质C系统的结构和功能进行卓越的可视化和预测（AIM 3）。具体而言，他将首先使用创伤/冲击的小鼠模型来确定创伤和灌注后蛋白质C中扰动的时间和机制。其次，他将使用体内小鼠模型以及内皮细胞缺血再灌注的体外模型来测试补体在创伤和休克后蛋白质C激活中的作用。第三，他将利用蛋白质C途径的网络表示以及新建的蛋白质C的动态模型，以模拟创伤后的蛋白质C途径中的蛋白质C途径。这些实验中获得的信息将在人类中具有重要的治疗意义。创伤患者的初步数据构成了本赠款申请的基本原理，表明凝血和补体异常在创伤后开始早期，并且与显着的发病率和死亡率增加有关。因此，了解与创伤后凝血和补体异常相关的分子和系统水平机制可能为创伤患者的治疗提供新的途径。这里的担忧是该模型确实复制了患者在临床上遇到的内容的元素。典型的创伤患者不仅因血管内量损失而遭受损失，但会导致组织损伤。受损的组织代表了损伤负担的重要组成部分，并导致损伤后的dyshomeostasis。这将如何影响申请人直接考虑实验模型输出的解释。 AIM 3需要根据AIM 1和2数据的结果进行动态建模，因此是一种有趣的方法。问题是如何将其证实为反映创伤患者发生的情况？

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cause and timing of death in massively transfused trauma patients.

DOI：
10.1097/ta.0b013e31829a24b4
发表时间：
2013-08
期刊：
The journal of trauma and acute care surgery
影响因子：
0
作者：
Cripps MW;Kutcher ME;Daley A;McCreery RC;Greenberg MD;Cachola LM;Redick BJ;Nelson MF;Cohen MJ
通讯作者：
Cohen MJ

Prohemostatic interventions in trauma: resuscitation-associated coagulopathy, acute traumatic coagulopathy, hemostatic resuscitation, and other hemostatic interventions.

创伤中的促止血干预：复苏相关性凝血病、急性创伤性凝血病、止血复苏和其他止血干预措施。