Dysregulation of Platelet-von Willebrand Factor Interaction in Trauma-Induced Coagulopathy

创伤性凝血病中血小板-血管性血友病因子相互作用的失调

• 批准号: 9888677
• 负责人: Alexander St. John
• 金额: $ 16.11万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9888677
• 关键词: Acetylcysteine; Actins; Adhesions; Affect; Animal Model; Binding; Blood; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Blood flow; Blood specimen; Brain Injuries; Career Mobility; Cause of Death; Cell membrane; Cessation of life; Cleaved cell; Clinical; Complex; Complication; Consumption; Data; Defect; Deposition; Diagnosis; Diagnostic; Disease; Disintegrins; Endothelial Cells; Fibrin split products; Fibrinogen; Functional disorder; Gelsolin; Goals; Hemorrhage; Hemostatic function; Imaging Device; Impairment; Injury; Integrins; Investigation; Knowledge; Lead; Learning; Ligands; Link; Malignant Neoplasms; Measurement; Measures; Mechanics; Mentors; Metalloproteases; Microcirculation; Modeling; Morbidity - disease rate; Myocardial Ischemia; Normalcy; Outcome; Oxidative Stress; Oxides; Pathway interactions; Patients; Peptide Hydrolases; Perfusion; Plasma; Platelet Activation; Platelet Adhesiveness; Platelet aggregation; Polymers; Process; Professional Competence; Proteins; Rattus; Research; Research Personnel; Sampling; Scientist; Shock; Structure; Surface; Syndrome; Techniques; Testing; Therapeutic Intervention; Thrombosis; Thrombospondins; Thrombus; Tissues; Training; Trauma; Trauma patient; Ultrasonography; United States; Work; acronyms; burden of illness; career; contrast enhanced; disability-adjusted life years; experimental study; improved; improved outcome; in vivo; injured; insight; knowledge base; member; mortality; multidisciplinary; oxidation; platelet function; polymerization; preventable death; receptor; severe injury; skills; von Willebrand Factor

PROJECT SUMMARY/ABSTRACT The overall goal of this project is to improve the outcomes of injured patients with trauma-induced coagulopa- thy (TIC), both by performing detailed investigation of the mechanisms underlying this disorder and by providing a junior clinician-scientist the training required to continue this work as an independent researcher. Trauma is the leading cause of disability-adjusted life-years (a measure of overall disease burden), both in the United States and worldwide. In trauma patients, hemorrhage is the leading cause of potentially preventable death. TIC is a common complication of serious injury that impairs normal hemostasis and contributes to the burden of death from hemorrhage. Two prominent features of TIC are impairment of platelet adhesion and aggregation function and derangement of microvascular blood flow. The causes of these abnormalities are not known, but preliminary data suggest several possible contributors. First, trauma patients have changes in their plasma von Willebrand factor (VWF) profiles that suggest high levels of endothelial cell activation and VWF secretion. Second, trauma patients have high levels of oxidative stress, which is known to make VWF hyperadhesive. Third, trauma patients have low levels of gelsolin, a protein that normally solubilizes actin polymers, which can obstruct microvascular blood flow and promote thrombus formation. Other disease states that involve similar pathways have associated microthrombus formation leading to microvascular blood flow changes similar to those seen in TIC. Finally, three key surface receptors that serve as mechanical anchors for platelets (GPIbα, αIIbβ3, and GPVI) show alterations in number and structure. Together, this suggests that the VWF-platelet adhesion axis mechanistically contrib- utes to platelet function impairment and microcirculation derangement through microvascular thrombosis and platelet receptor cleavage or occupancy. This project includes a set of experiments to elucidate the underlying causes of the platelet and microvascular changes of TIC. In Aim 1, the defects in the VWF-platelet adhesion axis will be characterized by detailed study of the changes that occur with VWF, its primary cleaving protein (ADAMTS13), and platelet adhesiveness in trauma patient blood samples. Aim 2 will characterize the alterations of platelet receptors GPIbα, αIIbβ3, and GPVI seen in TIC by testing for receptor occupancy and for receptor cleavage and loss in trauma patient samples. Aim 3 will evaluate the effects of agents that decrease VWF- platelet adhesion and actin polymerization on microvascular blood flow and clinical outcomes using contrast- enhanced ultrasound in a rat model of TIC. In addition to filling critical knowledge gaps in the pathophysiology of TIC, this project will allow the PI to develop advanced research career skills. Under a multidisciplinary team of expert mentors, the PI will gain a comprehensive conceptual and practical knowledge base in primary hemo- stasis, learn how to apply a powerful ultrasound imaging tool in an animal model, and complete career advance- ment activities to generate a unique expertise that will empower his future research. Ultimately, this project will both advance our knowledge of TIC and catalyze a junior investigator's transition to independence.

项目摘要/摘要 该项目的总体目标是改善创伤后凝血障碍患者的预后。 THY(TIC)，通过对这种疾病的潜在机制进行详细调查，并通过提供 初级临床医生兼科学家作为独立研究人员继续这项工作所需的培训.创伤是 致残的主要原因-调整后的寿命年(衡量总体疾病负担的指标)，在美国 以及世界范围内。在创伤患者中，出血是潜在的可预防死亡的主要原因。TiC是一种 严重损伤的常见并发症，损害正常止血并增加死亡负担 死于出血。TIC的两个显著特征是血小板黏附和聚集功能受损 以及微血管血流紊乱。这些异常的原因尚不清楚，但初步 数据显示有几个可能的贡献者。首先，创伤患者的血浆von Willebrand会发生变化 因子(VWF)特征提示高水平的内皮细胞激活和VWF分泌。第二，创伤 患者有高水平的氧化应激，这是已知的使VWF过度粘连的原因。第三，创伤患者 有低水平的明胶蛋白，这是一种蛋白质，通常可以溶解肌动蛋白聚合物，这可能会阻碍微血管 血液流动，促进血栓形成。其他涉及类似途径的疾病状态也与 微血栓形成导致微血管血流改变，与TIC相似。最后，三个 作为血小板机械锚的关键表面受体(GPIBα，αIIbβ3和GPVI)显示变化 在数量和结构上。综上所述，这表明VWF-血小板粘附轴是机械干扰的。 通过微血管血栓形成和微循环障碍导致的血小板功能损害和微循环障碍 血小板受体断裂或占位。这个项目包括一系列实验，以阐明潜在的 TIC的血小板和微血管改变的原因。在目标1中，VWF-血小板黏附的缺陷 Axis将通过详细研究其主要裂解蛋白VWF发生的变化来表征 (ADAMTS13)，以及创伤患者血液样本中的血小板粘附性。目标2将描述这些变化的特征 血小板受体GPIBα，αIIbβ3和GPVI在TIC中的受体占有率和受体检测 创伤患者样本中的卵裂和丢失。AIM 3将评估降低VWF的药物的效果- 对比研究血小板黏附和肌动蛋白聚合对微血管血流和临床结果的影响 大鼠TIC模型的超声增强。除了填补病理生理学方面的关键知识空白 对于TIC，这个项目将使PI能够发展高级研究职业技能。在一个多学科团队下 在专家导师的指导下，PI将获得全面的初级血液概念和实践知识基础。 停滞，学习如何在动物模型中应用强大的超声成像工具，并完成职业发展- 这些活动将产生独特的专业知识，这将为他未来的研究提供支持。最终，这个项目将 两者都促进了我们对TIC的了解，并促进了初级调查员向独立的过渡。