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

项目总结/摘要 该项目的总体目标是改善创伤性凝血功能障碍患者的预后， thy（TIC），通过对这种疾病的潜在机制进行详细研究，并提供 作为一名初级临床科学家，他接受了作为一名独立研究人员继续这项工作所需的培训。创伤是 残疾调整寿命年（衡量总体疾病负担的指标）的主要原因，无论是在美国， 和世界各地。在创伤患者中，出血是潜在可预防死亡的主要原因。TIC是一个 严重损伤的常见并发症，损害正常止血并导致死亡负担 因为出血血小板粘附和聚集功能受损是TIC的两个显著特征 和微血管血流紊乱。这些异常的原因尚不清楚，但初步 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因子 在一些实施方案中，VWF的特征表明高水平的内皮细胞活化和VWF分泌。第二，创伤 患者具有高水平的氧化应激，这是已知的使VWF超粘附。三、创伤患者 有低水平的凝溶胶蛋白，一种蛋白质，通常溶解肌动蛋白聚合物，这可能会阻碍微血管 促进血液流动和血栓形成。涉及类似途径的其他疾病状态与 微血栓形成导致微血管血流变化，类似于TIC中所见。最后，三 作为血小板机械锚的关键表面受体（GPIbα、αIIbβ3和GPVI）显示出改变 数量和结构。总之，这表明VWF-血小板粘附轴在机制上有助于 通过微血管血栓形成导致血小板功能受损和微循环障碍， 血小板受体裂解或占据。该项目包括一系列实验，以阐明 TIC血小板和微血管改变的原因。在目的1中，VWF-血小板粘附的缺陷 轴将通过详细研究其主要裂解蛋白VWF发生的变化来表征 （ADAMTS 13）和创伤患者血液样品中的血小板聚集。目标2将描述变更 血小板受体GPIbα、αIIbβ3和GPVI在TIC中观察到， 创伤患者样本中的分裂和丢失。目的3将评估降低VWF的药物的作用。 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， 增强超声在大鼠模型的TIC。除了填补病理生理学的关键知识空白外， 该项目将使PI发展先进的研究职业技能。在一个多学科的团队 专家导师，PI将获得一个全面的概念和实践知识基础，在初级血液， 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- 管理活动，以产生一个独特的专业知识，这将使他未来的研究。最终，该项目将 都推进我们的TIC知识和催化初级研究者的过渡到独立。

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.