Traumatic Brain Injury-induced Coagulopathy

描述(申请人提供)：创伤是凝血障碍的常见原因，主要是由于失血、液体复苏引起的血液稀释以及损伤引起的高凝状态所致的消耗。与躯干和四肢损伤的患者相比，创伤性脑损伤(TBI)患者的凝血障碍发生率很高，尽管这些患者的出血量要少得多，并接受有限的液体复苏，这表明TBI相关凝血障碍(TBI-AC)遵循一个独特的、但不明确的病理过程。脑组织中含有高度丰富的关键凝血分子；但这些脑源性分子在脑损伤-AC发病机制中的作用尚不清楚。我们的初步数据显示，机械损伤促进神经元和神经胶质细胞释放表达组织因子和磷脂酰丝氨酸的微粒，这些微粒在促进凝血方面具有积极作用。这些结果使我们假设：1)损伤的脑组织通过破坏的血脑屏障向血液循环释放促凝血剂分子；2)这些分子在脑外伤早期启动和传播高凝状态；3)这种过度的凝血迅速转变为消耗性凝血障碍。我们建议在探索性的初步研究中检验这些新的假设，以实现两个特定的目标。目的1检测单纯躯体创伤、单纯性脑外伤和多发伤合并脑外伤患者血液中脑源性促凝血分子的水平和活性。我们将分析这些患者的血浆样本，以确定脑源性促凝血微粒和PS结合清道夫蛋白的存在和活性。然后，我们将确定这些结果是否区分有凝血障碍和无凝血障碍的脑外伤患者。目的2是利用流体冲击致脑损伤的模型进行补充的小鼠研究，以克服在患者中机械性研究TBI-AC的局限性。我们建议研究1)促凝血剂微粒从脑外伤脑内释放到血液循环及其与血脑屏障损伤的关系，2)氧化修饰对脑磷脂促凝血活性的影响，以及3)外源性PS结合分子在降低这种促凝血活性中的作用。本探索性研究将探讨脑源性促凝血微粒在脑损伤-AC发病机制中作用的可行性和科学有效性。这将为开发一项旨在了解TBI-AC机制并确定新的治疗靶点的研究奠定基础，该治疗靶点可以在对止血影响最小的情况下逆转凝血障碍的进程。

DESCRIPTION (provided by applicant): Trauma is a common cause of coagulopathy, primarily due to blood loss, hemodilution secondary to fluid resuscitation, and consumption due to injury-induced hyper-coagulation. A high incidence of coagulopathy is found in patients with traumatic brain injury (TBI), even though these patients bleed far less and receive restricted flui resuscitation as compared to patients with injury to the trunk and limbs, suggesting that TBI- associated coagulopathy (TBI-AC) follows a distinct, but poorly defined, pathological course. Brain tissue is highly enriched in key coagulant molecules; but the contribution of these brain-derived molecules to the pathogenesis of TBI-AC is not known. Our preliminary data show that mechanical injury promotes neurons and glial cells to release microparticles that express tissue factor and phosphatidylserine that are active in promoting coagulation. These results led us to hypothesize that 1) injured cerebral tissue releases procoagulant molecules into the circulation through the disrupted blood-brain barrier; 2) these molecules initiate and propagate a hyper-coagulable state in the early stages of TBI; and 3) this exaggerated coagulation is rapidly transited into consumptive coagulopathy. We propose to test these novel hypotheses in an exploratory pilot study by achieving two specific aims. Aim 1 is to measure levels and activity of brain-derived procoagulant molecules in blood samples from patients with only body trauma, isolated TBI and polytrauma with TBI. We will analyze plasma samples from these patients for the presence and activity of the brain-derived procoagulant microparticles and PS-binding scavenger proteins. We will then determine if these results distinguish between TBI patients with and without coagulopathy. Aim 2 is to conduct a complementary mouse study using a model of fluid percussion injury to the brain in order to overcome limitations associated with mechanistically studying TBI-AC in patients. We propose to examine 1) release of procoagulant microparticles from the TBI brain to the circulation and its association with injury to the blood-brain barrier, 2) impact of oxidative modifications on the procoagulant activity of brain phospholipids, and 3) the role of exogenous PS- binding molecules in reducing this procoagulant activity. This exploratory study will examine the feasibility and scientific validity f studying roles of brain-derived procoagulant microparticles in the pathogenesis of TBI-AC. It will lay the foundation for developing a study designed to understand the mechanisms of TBI-AC and identify new therapeutic targets that could reverse the course of coagulopathy with a minimal impact on hemostasis.