Traumatic Brain Injury-induced Coagulopathy

描述（由申请人提供）：创伤是凝血功能障碍的常见原因，主要是由于失血、液体复苏后的血液稀释和损伤引起的高凝血消耗。与躯干和四肢损伤的患者相比，外伤性脑损伤（TBI）患者凝血功能障碍的发生率很高，尽管这些患者出血少得多，并且接受了限制性的流感复苏，这表明TBI相关凝血功能障碍（TBI- ac）遵循一个明确但不明确的病理过程。脑组织中富含关键的凝血分子；但这些脑源性分子在TBI-AC发病机制中的作用尚不清楚。我们的初步数据表明，机械性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，这些微粒具有促进凝血的活性。这些结果使我们假设：1)受伤的脑组织通过被破坏的血脑屏障释放促凝剂分子进入血液循环；2)这些分子在TBI早期启动并传播高凝状态；3)这种夸大的凝血会迅速转变为消耗性凝血病。我们建议通过实现两个具体目标，在探索性试点研究中检验这些新颖的假设。目的1是测量单纯性创伤、孤立性TBI和多发创伤合并TBI患者血液样本中脑源性促凝剂分子的水平和活性。我们将分析这些患者的血浆样本中脑源性促凝剂微粒和ps结合清除蛋白的存在和活性。然后我们将确定这些结果是否可以区分有凝血功能障碍和没有凝血功能障碍的TBI患者。目的2是使用脑液体冲击损伤模型进行一项补充性小鼠研究，以克服与TBI-AC患者机制研究相关的局限性。我们建议研究1)脑外伤后促凝微粒向血液循环的释放及其与血脑屏障损伤的关系，2)氧化修饰对脑磷脂促凝活性的影响，以及3)外源性PS结合分子在降低这种促凝活性中的作用。本探索性研究将检验脑源性促凝剂微颗粒在TBI-AC发病机制中作用的可行性和科学有效性。这将为开展一项旨在了解TBI-AC机制的研究奠定基础，并确定新的治疗靶点，从而在对止血影响最小的情况下逆转凝血病的进程。

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.