Mechanisms of microvascular thrombosis in inflammation

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.