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von Willebrand Factor in Traumatic Brain Injury and Associated Coagulopathy

外伤性脑损伤和相关凝血病中的冯维勒布兰德因子

基本信息

批准号：
10599316
负责人：
Jing-Fei Dong
金额：
$ 65.79万
依托单位：
BLOODWORKS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599316
关键词：
ADAMTS Acute Acute Brain Injuries Adhesives Apoptotic Autoimmune Diseases Blood Blood Coagulation Disorders Blood Platelets Blood Vessels Brain Brain Injuries Cardiolipins Cardiovascular Diseases Cells Cephalic Cerebrum Circulation Clinical Clinical Management Coagulation Process Cohort Studies Complication Confounding Factors (Epidemiology)Development Diagnosis Disease Disease susceptibility Disintegrins Early identification Endothelial Cells Endothelium Environment Enzymes Extravasation Factor VIII-Related Antigen Goals Hemodilution Hemorrhage Hemorrhagic Shock Hemostatic Agents Hemostatic function Impairment In Vitro Inflammation Injury Laboratories Life Ligands Limb structure Liquid substance Malignant Neoplasms Measurement Measures Mechanics Mediating Metalloproteases Mitochondria Molecular Conformation Multiple Trauma Multivariate Analysis Mus Nervous System Physiology Outcome Pathologic Pathway interactions Patients Peptide Hydrolases Phospholipids Plasma Platelet Activation Prevention Proteins Reactive Oxygen Species Resuscitation Role Sampling Severities Surface TBI Patients Testing Thrombophilia Thromboplastin Thrombospondins Transfusion Trauma Trauma patient Traumatic Brain Injury Variant blood-brain barrier disruption clinically relevant design efficacy study experimental study extracellular extracellular vesicles improved improved outcome microvesicles mouse model natural hypothermia new therapeutic target novel marker oxidation predictive marker prevent release factor respiratory therapeutically effective vascular injury vesicular release von Willebrand Disease von Willebrand Factor

项目摘要

Project Summary Traumatic brain injury is commonly associated with the inability of blood to clot (coagulopathy), resulting in secondary or delayed systemic and intracranial bleeding. Substantial blood loss, hemodilution due to fluid resuscitation, and hypothermia are the most common causes of coagulopathy associated with trauma to the body and limbs and hemorrhagic shock. We have recently demonstrated that an injured brain releases extracellular vesicles (EVs) into circulation. These brain‐derived EVs induce a hypercoagulable state that quickly evolves into consumptive coagulopathy. Extracellular mitochondria (exMTs) are also released into circulation and promote coagulation through the surface‐exposed mitochondrial phospholipid cardiolipin. ExMts also maintain the respiratory activity to generate reactive oxygen species that activate platelets and endothelial cells. These findings demonstrate that TBI induces consumptive coagulopathy that is mechanistically distinct from deficient and dilutional coagulopathy associated with extracranial trauma and hemorrhagic shock. Our recent study further implicates the adhesive ligand von Willebrand factor (VWF) for mediating EV‐induced vascular injury and for activating platelets to propagate coagulopathy in mouse models of traumatic brain injury. These recently findings led us to hypothesize that: 1) brain‐derived EVs released from injured brains stimulate endothelial cells to release hyper‐adhesive VWF multimers that are not timely and sufficiently cleaved by the enzyme ADAMTS13, 2) these hyper‐adhesive VWF multimers facilitate EV‐ induced vascular leakage and propagate EV‐induced coagulopathy, and 3) the hyper‐adhesive activity of VWF can be selectively blocked in acute brain injury without reducing the hemostatic activity of VWF. Here, we propose testing these hypotheses in two specific aims. The first is to study ADAMTS‐13 variants, the VWF A2 domain, and the apoptotic cell‐scavenging molecule Del‐1 for blocking the TBI‐induced hyper‐adhesive activity of VWF to protect mice from developing traumatic brain injury‐induced coagulopathy, and to define the underlying mechanisms of their actions in mouse models. The second is to conduct a cohort study of 120 patients with TBI and trauma controls to determine the clinical relevance of findings from the mouse study. We will analyze patient samples to quantify VWF activity and ADAMTS‐13 cleavage as primary variables and to define platelet activation, plasma levels of EVs and clinical coagulopathy as outcome variables. We will associate primary variables to outcome variables through multivariate analyses to define a causal role of hyper‐adhesive VWF in traumatic brain injury‐induced coagulopathy and to develop new markers for predicting the coagulopathy with focus on VWF hyper‐reactivity and EV clearance. This study is an integral part of our long‐term goal to define the systemic impact of traumatic brain injury and to study a role of the traumatic brain injury‐induced systemic changes in propagating secondary cerebral injury.

项目摘要创伤性脑损伤通常与血液不能凝结（凝血病）相关，导致继发性或迟发性全身和颅内出血。大量失血，液体导致血液稀释复苏和体温过低是与创伤相关的凝血病的最常见原因。和失血性休克。我们最近证明了受伤的大脑会释放细胞外囊泡（EV）进入循环。这些脑源性EV诱导高凝状态，很快就会发展成消耗性凝血功能障碍细胞外线粒体（exMT）也被释放到细胞内。通过表面暴露的线粒体磷脂心磷脂促进血液循环和凝血。 ExMts还维持呼吸活性以产生活化血小板的活性氧物质，内皮细胞这些发现表明，TBI诱导消耗性凝血病，与颅外创伤相关的凝血功能缺陷和稀释性凝血病不同，失血性休克我们最近的研究进一步表明，粘附配体血管性血友病因子（VWF）在小鼠模型中介导EV诱导的血管损伤并激活血小板以传播凝血病创伤性脑损伤这些最近的发现使我们假设：1）脑源性EV释放从受伤的大脑刺激内皮细胞释放超粘附VWF多聚体，并被酶ADAMTS 13充分切割，2）这些高粘附性VWF多聚体促进EV- 诱导血管渗漏并传播EV诱导的凝血病，以及3）VWF的高粘附活性在急性脑损伤中可被选择性阻断而不降低VWF的止血活性。这里我们我建议在两个具体目标中检验这些假设。首先是研究ADAMTS-13变异体，即VWF A2 结构域和凋亡细胞清除分子Del-1，用于阻断TBI诱导的高粘附 VWF保护小鼠免于发生创伤性脑损伤诱导的凝血病的活性，并定义它们在小鼠模型中作用的潜在机制。二是对120名 TBI患者和创伤对照，以确定小鼠研究结果的临床相关性。我们将分析患者样本，以定量VWF活性和ADAMTS-13裂解作为主要变量，将血小板活化、血浆EV水平和临床凝血病定义为结局变量。我们将通过多变量分析将主要变量与结果变量相关联，以确定高粘附性VWF在创伤性脑损伤诱导的凝血病中的作用，并开发新的标记物，预测凝血病，重点关注VWF高反应性和EV清除。这项研究是一个整体我们长期目标的一部分是确定创伤性脑损伤的全身影响，并研究脑损伤的作用。创伤性脑损伤诱导的继发性脑损伤传播的全身变化。