Enhanced venous thrombosis and hypercoagulability in murine and human metabolic dysfunction-associated steatohepatitis
Nilesh Pandey 1), Sumit Kumar Anand 1), Harpreet Kaur 1), Koral S.E. Richard 1), Lakshmi Chandaluri 1), Megan E. Butler 2), Xiaolu Zhang 3), Brenna Pearson-Gallion 2), Sumati Rohilla 1), Sandeep Das 1), Tarek Magdy 1), Palaniappan Sethu 4), Kelley G. Núñez 5), A. Wayne Orr 1) 2), Karen Y. Stokes 2), Paul T. Thevenot 5), Ari J. Cohen 5) 6), Oren Rom 1) 2), Nirav Dhanesha 1)
1) Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
2) Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
3) Bioinformatics and Modeling Core, The Center for Applied Immunology and Pathological Processes, Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
4) Division of Cardiovascular Disease, Department of Medicine, School of Medicine and Department of Biomedical Engineering, School of Engineering, University of Alabama at Birmingham, Birmingham, Alabama, USA
5) Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
6) Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
Abstract
Introduction
Patients with metabolic dysfunction-associated steatohepatitis (MASH) are at an increased risk of developing venous thromboembolic events, 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 pathologic 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 standard chow diet or a high-fructose, high-fat, and high-cholesterol MASH diet for 24 weeks. Plasma analyses of coagulation markers and thrombin generation assays 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 levels of 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 = .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 levels of 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 venous thromboembolic events in patients with MASH.