Traumatic Brain Injury-induced Coagulopathy

描述（由申请方提供）：创伤是凝血功能障碍的常见原因，主要是由于失血、液体复苏继发的血液稀释和损伤诱导的高凝状态引起的消耗。在患有创伤性脑损伤（TBI）的患者中发现凝血病的高发病率，即使与躯干和四肢损伤的患者相比，这些患者出血少得多并且接受限制性液体复苏，这表明TBI相关的凝血病（TBI-AC）遵循独特的但不明确的病理过程。脑组织高度富集关键凝血分子;但这些脑源性分子对TBI-AC发病机制的贡献尚不清楚。我们的初步数据表明，机械损伤促进神经元和神经胶质细胞释放微粒，表达组织因子和磷脂酰丝氨酸，积极促进凝血。这些结果使我们假设：1）受损的脑组织通过破坏的血脑屏障将促凝分子释放到循环中; 2）这些分子在TBI的早期阶段引发并传播高凝状态; 3）这种过度的凝血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测试这些新的假设。目的1是测量来自仅具有身体创伤、孤立性TBI和多发性创伤合并TBI的患者的血液样品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中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功能障碍和无凝血功能障碍的TBI患者。目的2是使用脑液压冲击损伤模型进行补充小鼠研究，以克服与在患者中机械研究TBI-AC相关的局限性。我们建议检查1）促凝血微粒从TBI脑到循环的释放及其与血脑屏障损伤的相关性，2）氧化修饰对脑磷脂促凝血活性的影响，和3）外源性PS结合分子在降低该促凝血活性中的作用。本研究旨在探讨脑源性促凝微粒在TBI-AC发病机制中作用的可行性和科学有效性。它将为开发旨在了解TBI-AC机制的研究奠定基础，并确定新的治疗靶点，这些靶点可以逆转凝血病的过程，对止血的影响最小。

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.