Mechanisms of microvascular thrombosis in inflammation

血栓形成和炎症（或血栓炎症）在多种疾病中相互关联 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（COVID-19）。脓毒症通常是最常见的个人入院诊断， VA系统的重症监护病房，尽管在2020年的某些星期，COVID-19 到目前为止，在我们的VA医疗中心和其他医院， 在VA系统中。尽管重症监护医学取得了进展，但脓毒症和COVID-19仍然存在 作为危及生命的疾病，导致显著的发病率、死亡率和高 全世界退伍军人和非退伍军人的经济负担。COVID-19和败血症都是 与微血管血栓形成和凝血病相关，在这两种情况下， 凝血病的严重程度与死亡率的增加有关。因此，理解 脓毒症等全身性炎症中微血管血栓形成的机制 和COVID-19，对VA医疗保健系统具有重要的临床意义。最近的工作 从我们的实验室证明，细胞质中间蛋白的细胞外形式， 在血浆中循环的波形蛋白在实验性血栓形成中起重要作用， COVID-19和脓毒症诱导的凝血病中的纤维蛋白聚合。本申请旨在 了解血浆波形蛋白在血栓形成和纤维蛋白聚合中的作用， 炎症我们的中心假设是，血浆波形蛋白介导微血管 败血症和COVID-19中的血栓形成通过增强凝血酶诱导的纤维蛋白聚合。 本研究的目的有两个：目的1：研究血浆波形蛋白在微血管形成中的作用。 小鼠血栓形成和退伍军人COVID-19和脓毒症诱导的纤维蛋白聚合 凝血病目的2将明确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异性起源。完成拟议的实验将扩大 我们对脓毒症中炎症和微血管血栓形成之间联系的理解， COVID-19，并将为未来旨在预防微血管的工作提供基础 全身炎症中血栓形成。长期目标是开发最佳治疗方法， 脓毒症、COVID-19和其他与 血栓炎

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.