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: 10352212
• 负责人: Alexander St. John
• 金额: $ 15.63万
• 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/10352212
• 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; 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; trauma induced coagulopathy; ultrasound; 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 该项目的总体目的是改善受伤诱导的凝结蛋白蛋白蛋白酶的受伤患者的结局。 通过对这种疾病背后的机制进行详细研究，并提供 初级临床科学家是继续作为独立研究人员继续这项工作所需的培训。创伤是 在美国，造成残疾调整的生命年的主要原因（衡量整体疾病伯恩） 和全球。在创伤患者中，出血是可能预防死亡的主要原因。抽动是 严重伤害的常见并发症会损害正常止血并导致死亡的灼伤 从出血。抽动的两个突出特征是血小板粘附和聚集功能的损害 和微血管血流的进化。这些异常的原因尚不清楚，但初步 数据表明几个可能的贡献者。首先，创伤患者的血浆von Willebrand发生变化 因子（VWF）曲线，表明高水平的内皮细胞激活和VWF分泌。第二，创伤 患者的氧化应激水平很高，已知可以使VWF高粘着性。第三，创伤患者 凝胶素水平较低，凝胶素是一种通常溶解肌动蛋白聚合物的蛋白质，可以阻塞微血管 血流并促进血栓形成。其他涉及类似途径的疾病状态已与 微树形的形成导致微血管血流的变化类似于TIC中的微血管。最后，三个 用作血小板机械锚的关键表面受体（GPIBα，αIIBβ3和GPVI）显示改变 数量和结构。总之，这表明VWF-Platelet粘附轴机械地贡献 通过微血管血栓形成和 血小板受体的裂解或占用率。该项目包括一组阐明基础的实验 血小板和微血管变化的原因。在AIM 1中，VWF - 划线粘附中的缺陷 轴将以详细的研究对VWF发生的变化进行详细研究，其主要分裂蛋白 （ADAMTS13）和创伤患者血液样本中的血小板粘附性。 AIM 2将描述更改 通过测试受体占用和受体，在TIC中看到的血小板受体GPIBα，αIIBβ3和GPVI 创伤患者样本的裂解和损失。 AIM 3将评估降低VWF-的代理的影响 血小板粘附和肌动蛋白聚合在微血管血流和临床结果上使用对比 在大鼠TIC模型中增强了超声。除了填补病理生理学的关键知识差距 在TIC中，该项目将使PI能够发展高级研究职业技能。在一个多学科团队中 在专家导师中，PI将在原发性血液中获得全面的概念和实践知识基础 停滞，学习如何在动物模型中应用功能强大的超声成像工具，并完成职业发展 - 旨在产生独特的专业知识，以增强他未来的研究能力。最终，这个项目将 两者都促进了我们对抽动的了解，并促进了初级调查员向独立的过渡。