AHA CDA data deposit

To evaluate the severity of venous thrombosis in MASH, we utilized mice fed on established MASH diet that closely mimic histological and transcriptional aspects of human disease. We evaluated hepatic fibrosis and steatohepatitis, analyzed plasma levels of coagulations markers, performed unbiased RNA-seq of the liver samples, and evaluated DVT severity using the inferior vena cava (IVC) partial ligation model. Additionally, we utilized a well-characterized cohort of patients with MASH and controls to analyze plasma levels of coagulations markers and to perform a thrombin generation assay. In this study, we provide evidence of exacerbated DVT severity and hypercoagulability in mice and human with MASH, respectively. Using a dietary mouse model of MASH that exhibits a coexistence of steatosis and fibrosis, we found a significant upregulation of pathways related to inflammation and coagulation using unbiased RNA-seq of liver samples. Additionally, the mice fed on a MASH diet exhibited increased plasma markers of coagulation and exacerbated DVT severity following IVC stenosis. Finally, using a well-defined cohort of MASH patients and age –, sex –, and race –matched controls, we found the evidence of significantly increased plasma markers of coagulation and delayed plasma thrombin generation. Our novel MASH-DVT model can facilitate a better understanding of the fundamental mechanisms leading to increased VTE in patients with MASH.<br>sing pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin a9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in a9fl/flMrp8Cre+/- mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin a9.<br><br>