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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该项目的总体目标是改善因创伤引起的凝血障碍的受伤患者的结果 thy (TIC)，通过对这种疾病的潜在机制进行详细调查并提供作为一名初级临床医生科学家，作为独立研究员继续这项工作所需的培训是。在美国，残疾调整生命年（总体疾病负担的衡量标准）的主要原因在世界范围内，出血是导致 TIC 死亡的主要原因，而这种死亡是可以预防的。严重损伤的常见并发症，会损害正常止血并导致死亡负担 TIC 的两个显着特征是血小板粘附和聚集功能受损。这些异常的原因尚不清楚，但初步确定。数据表明，有几个可能的因素：首先，创伤患者的血浆血管性血友病发生了变化。因子 (VWF) 谱表明内皮细胞活化和 VWF 分泌水平较高。其次，创伤。患者存在高水平的氧化应激，这会导致 VWF 过度粘附。第三，创伤患者。凝溶胶蛋白水平低，凝溶胶蛋白是一种通常溶解肌动蛋白聚合物的蛋白质，可阻塞微血管涉及类似途径的其他疾病状态也与之相关。微血栓形成导致微血管血流变化，类似于 TIC 中所见的情况。最后，三个。作为血小板机械锚的关键表面受体（GPIbα、αIIbβ3 和 GPVI）显示出变化总的来说，这表明 VWF-血小板粘附轴在机械上有贡献。通过微血管血栓形成导致血小板功能受损和微循环紊乱血小板受体裂解或占据该项目包括一组实验来阐明其根本原因。 TIC 血小板和微血管变化的原因在目标 1 中，VWF-血小板粘附缺陷。轴的特点是详细研究 VWF（其主要裂解蛋白）发生的变化 (ADAMTS13) 和创伤患者血液样本中的血小板粘附性将表征这些变化。通过测试受体占用和受体，在 TIC 中观察到血小板受体 GPIbα、αIIbβ3 和 GPVI 目标 3 将评估减少 VWF- 的药物的效果。血小板粘附和肌动蛋白聚合对微血管血流和临床结果的影响除了填补病理生理学方面的关键知识空白之外，还对 TIC 大鼠模型进行了增强超声检查。 TIC 的该项目将使 PI 在多学科团队的领导下培养高级研究职业技能。由专家导师组成，PI 将获得初级血液学方面的全面概念和实践知识基础停滞期，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—— 最终，该项目将产生独特的专业知识，为他未来的研究提供支持。两者都增进了我们对 TIC 的了解，并促进初级研究者向独立的过渡。