Enhanced Venous Thrombosis and Hypercoagulability in Murine and Human Metabolic Dysfunction-Associated Steatohepatitis.

ABSTRACT

BACKGROUND: Patients with metabolic dysfunction-associated steatohepatitis (MASH) are at an increased risk of developing venous thromboembolic events (VTE), including deep vein thrombosis (DVT). To date, the study of DVT in MASH has been hampered by the lack of reliable models that mimic the pathological aspects of human disease. OBJECTIVES: To evaluate DVT severity and hypercoagulability in murine and human MASH. METHODS: Transcriptional changes in the liver, plasma markers of coagulation, and DVT severity were evaluated in mice fed a chow diet or a high-fructose, high-fat, and high-cholesterol, MASH diet for 24 weeks. Plasma analyses of coagulations markers and thrombin generation assay were performed in a well-characterized cohort of patients with or without MASH. RESULTS: Mice fed the MASH diet developed steatohepatitis and fibrosis, mimicking human MASH. Liver RNA-sequencing revealed a significant upregulation of pathways related to inflammation and coagulation concomitant with increased plasma coagulation markers including increased prothrombin fragment 1+2, thrombin-antithrombin complex, plasminogen activator inhibitor-1 levels, and endothelin 1. MASH exacerbated DVT severity in mice, as evidenced by increased thrombus weight and higher thrombosis incidence (15/15 vs. 11/15 in controls, p=0.0317). Higher endothelin 1 release and increased apoptosis were found in endothelial cells stimulated with supernatants of palmitate-stimulated HepG2 cells. Patients with MASH exhibited increased plasma coagulation markers and delayed thrombin generation. CONCLUSION: We report enhanced DVT severity and hypercoagulability, both in murine and human MASH. Our model of MASH-DVT can facilitate a better understanding of the fundamental mechanisms leading to increased VTE in patients with MASH.