Thursday, April 25, 2024
4/25/2024
Project Summary Infection with severe acute respiratory syndrome novel corona virus (SARS-CoV-2) causes COVID-19. In severe cases, COVID-19 leads to profound inflammation (“cytokine storm”) followed by coagulopathy and a prothrombotic-state with progression to multiple organ failure. Several cytokines, including IL6 are elevated. Further, a proinflammatory galectin, Galectin-3 (Gal-3) is also found elevated. Gal-3 upregulates IL6 and other cytokines, can directly activate platelets, neutrophils, and endothelial cells, and is known to mediate venous thrombosis via IL6 in a mouse model. A growing body of literature has implicated neutrophil, platelet and endothelial cell activation as potential drivers of thrombotic complications in COVID-19 patients. However, there are no direct mechanistic links established between inflammation, vascular cell activation, and thrombosis during SARS-CoV-2 infection. Our objective is to define the mediators that cause activation of neutrophils, platelets and/or endothelial cells during SARS-CoV-2 infection and their mechanistic roles in promoting thrombin generation and thrombosis. At the University of Iowa, we led a multicenter randomized clinical trial (RCT) comparing standard prophylactic dose to intermediate dose enoxaparin in hospitalized patients with COVID-19 (NCT04360824) and collected plasma samples for biomarkers and mechanistic studies. Given the upsurge in late thrombotic complications of COVID-19, we now propose to recruit additional patients to collect serial samples every week during hospitalization and thereafter every 3 months for up to 3 years. We hypothesize that thrombogenicity in COVID-19 is mediated by IL6- and Gal-3-driven activation of hematopoietic and endothelial cells and that the prothrombotic state persists even after recovery from viral infection. Our team has a unique combination of expertise and resources that will address the hypothesis in 2 well integrated but independent aims. In Aim 1, using serially collected patient’s samples, we will determine the mechanistic role of IL6, Gal-3, and NETs in mediating cellular activation and enhancing thrombin generation and thrombosis in COVID-19. Aim 2 will utilize a novel transgenic mouse model of SARS-CoV-2 infection to determine if targeting IL6, Gal-3, or NETs in vivo protects against cellular activation, thrombin generation and thrombosis. A strength of this proposal is in utilizing clinical samples and a novel preclinical model to identify critical mechanistic pathways for cellular activation, thrombin generation and in vivo thrombosis in COVID-19. Thus, the overall impact of the proposed research agenda is very high and is likely to provide therapeutic targets for decreasing thrombotic burden in COVID-19.
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