Mechanisms of microvascular thrombosis in inflammation

血栓形成和炎症(或血栓性炎症)在各种疾病中是相互关联的。 包括败血症或身体对感染的失调反应，以及新型冠状病毒 2019年(新冠肺炎)。败血症通常是最常见的个人入院诊断 退伍军人事务部重症监护病房，尽管在2020年的某些星期，新冠肺炎 到目前为止，我们退伍军人医学中心和其他机构的急性医学入院诊断领先 在退伍军人制度中。尽管重症监护医学取得了进展，但脓毒症和新冠肺炎仍然存在 因为危及生命的情况会导致严重的发病率、死亡率和高 世界各地退伍军人和非退伍军人的经济负担。新冠肺炎和败血症都是 与微血管血栓和凝血障碍有关，在这两种情况下， 凝血障碍的严重程度与死亡率的增加有关。因此，理解 脓毒症等全身炎症中微血管血栓形成的机制 和新冠肺炎，对退伍军人医疗体系具有重大临床意义。近期工作 从我们的实验室证明胞外形式的细胞质中间蛋白 血浆循环中的波形蛋白在实验性血栓形成中起着重要作用，并在 新冠肺炎和脓毒症所致凝血障碍中的纤维蛋白聚合。此应用程序的目标是 了解血浆波形蛋白在系统性红斑狼疮血栓形成和纤维蛋白聚合中的作用 发炎。我们的中心假设是血浆波形蛋白介导微血管 促进凝血酶诱导的纤维蛋白聚合在脓毒症和新冠肺炎中的血栓形成。 提出两个目标：目标1将确定血浆波形蛋白在微血管中的作用 新冠肺炎和脓毒症诱导的小鼠血栓形成和退伍军人纤维蛋白聚合 凝血障碍。目标2将定义波形蛋白及其细胞的翻译后修饰的作用- 微血管血栓形成的特定来源。拟议实验的完成将扩大 我们对脓毒症炎症与微血管血栓形成关系的认识 新冠肺炎，并将为今后旨在预防微血管的工作提供基础 全身炎症中的血栓形成。长期目标是开发出最佳的治疗方法。 脓毒症、新冠肺炎和其他相关疾病患者的治疗方法 血栓性炎症。

Thrombosis and inflammation (or thromboinflammation) are interrelated in a variety of illnesses including sepsis or the body’s dysregulated response to an infection, and the novel Coronavirus 2019 (COVID-19). Sepsis is typically the most common individual admission diagnosis in intensive care units in the VA system, although during certain weeks in 2020, COVID-19 was by far the leading acute medicine admission diagnosis at our VA Medical Center and others in the VA system. Despite advances in critical care medicine, sepsis and COVID-19 remain as life-threatening conditions resulting in significant morbidity, mortality, and a high economic burden in Veterans and non-Veterans worldwide. Both COVID-19 and sepsis are associated with microvascular thrombosis and coagulopathy and in both conditions, the severity of coagulopathy is associated with increased mortality rates. Thus, understanding the mechanisms of microvascular thrombosis in systemic inflammation such as sepsis and COVID-19, has major clinical significance to the VA health care system. Recent work from our laboratory demonstrate that an extracellular form of a cytoplasmic intermediate protein circulating in plasma, vimentin, plays important roles in experimental thrombosis, and mediates fibrin polymerization in COVID-19 and in sepsis-induced coagulopathy. This application aims to understand the role of plasma vimentin in thrombosis and fibrin polymerization in systemic inflammation. Our central hypothesis is that plasma vimentin mediates microvascular thrombosis in sepsis and COVID-19 via enhancing thrombin-induced fibrin polymerization. Two aims are proposed: Aim 1 will determine the role of plasma vimentin on microvascular thrombosis in mice and on fibrin polymerization in Veterans with COVID-19- and sepsis-induced coagulopathy. Aim 2 will define the role of post-translational modifications of vimentin and its cell- specific origin on microvascular thrombosis. Completion of the proposed experiments will broaden our understanding of the links between inflammation and microvascular thrombosis in sepsis and COVID-19, and will provide the basis for future work aimed at preventing microvascular thrombosis in systemic inflammation. The long-term goal is to develop optimal therapeutic approaches for patients with sepsis, COVID-19, and other diseases associated with thromboinflammation.