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

• 批准号: 10370366
• 负责人: Jing-Fei Dong
• 金额: $ 65.84万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370366
• 关键词: ADAMTS; Acute; Acute Brain Injuries; Adhesives; Apoptotic; Autoimmune Diseases; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Brain; Brain Injuries; Cardiolipins; Cardiovascular Diseases; Cells; Cerebrum; Clinical; Clinical Management; Coagulation Process; Cohort Studies; Complication; Confounding Factors (Epidemiology); Development; Diagnosis; Disease susceptibility; Disintegrins; 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; Lead; 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; Oxides; 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; clinically relevant; design; efficacy study; experimental study; extracellular; extracellular vesicles; improved; improved outcome; microvesicles; mouse model; natural hypothermia; new therapeutic target; novel marker; oxidation; preconditioning; predictive marker; prevent; release factor; respiratory; therapeutically effective; vascular injury; vesicular release; von Willebrand Disease; von Willebrand Factor

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.

项目概要 创伤性脑损伤通常与血液无法凝结（凝血病）有关，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障碍的最常见原因 身体和四肢失血性休克。我们最近证明受伤的大脑会释放 细胞外囊泡（EV）进入循环。这些脑源性 EV 会导致高凝状态 很快演变成消耗性凝血病。细胞外线粒体（exMT）也被释放到 通过表面暴露的线粒体磷脂心磷脂促进循环并促进凝血。 ExMts 还维持呼吸活动以产生活性氧，从而激活血小板和 内皮细胞。这些发现表明，TBI 会诱发消耗性凝血病，即 在机制上与颅外伤相关的缺陷性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冯维勒布兰德因子（VWF）对于 介导 EV 诱导的血管损伤并激活血小板以在小鼠模型中传播凝血病 的创伤性脑损伤。这些最近的发现使我们做出假设：1）释放的脑源性 EV 受伤大脑刺激内皮细胞不及时释放高粘附性 VWF 多聚体 并被 ADAMTS13 酶充分裂解，2）这些超粘附 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 的超粘附活性 可以选择性地阻断急性脑损伤而不降低 VWF 的止血活性。在这里，我们 建议在两个特定目标中测试这些假设。第一个是研究 ADAMTS-13 变体，VWF A2 结构域和凋亡细胞清除分子 Del-1，用于阻断 TBI 诱导的过度粘附 VWF 保护小鼠免受创伤性脑损伤诱发的凝血病的活性，并定义 它们在小鼠模型中作用的基本机制。第二个是对 120 人进行队列研究 患有 TBI 的患者和创伤对照，以确定小鼠研究结果的临床相关性。 我们将分析患者样本，以量化 VWF 活性和 ADAMTS-13 裂解作为主要变量， 将血小板活化、EV 血浆水平和临床凝血病定义为结果变量。我们将 通过多变量分析将主要变量与结果变量关联起来，以确定因果关系 超粘附 VWF 在创伤性脑损伤引起的凝血病中的应用，并开发新的标记物 预测凝血病，重点关注 VWF 高反应性和 EV 清除率。这项研究是一个完整的 我们长期目标的一部分是确定创伤性脑损伤的系统性影响并研究创伤性脑损伤的作用 创伤性脑损伤引起的继发性脑损伤传播的全身变化。