Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA.
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA.
J Thromb Haemost. 2024 Dec;22(12):3572-3580. doi: 10.1016/j.jtha.2024.08.023. Epub 2024 Sep 19.
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.
To evaluate DVT severity and hypercoagulability in murine and human MASH.
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.
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.
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.
代谢相关脂肪性肝炎（MASH）患者发生静脉血栓栓塞事件（包括深静脉血栓形成[DVT]）的风险增加。迄今为止，由于缺乏模拟人类疾病病理特征的可靠模型，MASH 患者 DVT 的研究受到阻碍。
评估小鼠和人类 MASH 中的 DVT 严重程度和高凝状态。
用标准的纤维饲料或高果糖、高脂肪、高胆固醇 MASH 饲料喂养小鼠 24 周，评估肝脏转录变化、凝血血浆标志物和 DVT 严重程度。对具有或不具有 MASH 的患者进行了凝血标志物的血浆分析和凝血酶生成测定。
用 MASH 饮食喂养的小鼠发生了脂肪性肝炎和纤维化，模拟了人类 MASH。肝脏 RNA 测序显示，与炎症和凝血相关的途径显著上调，同时血浆凝血标志物水平升高，包括凝血酶原片段 1+2、凝血酶-抗凝血酶复合物、纤溶酶原激活物抑制剂-1 水平和内皮素 1 升高。MASH 加重了小鼠的 DVT 严重程度，表现为血栓重量增加和血栓形成发生率升高（15/15 与对照组 11/15，P=0.0317）。用棕榈酸刺激 HepG2 细胞上清液刺激内皮细胞，发现内皮素 1 释放增加和细胞凋亡增加。MASH 患者的血浆凝血标志物水平升高，凝血酶生成延迟。
我们报告了 MASH 中 DVT 严重程度和高凝状态的增强，包括在小鼠和人类 MASH 中。我们的 MASH-DVT 模型可以帮助更好地理解导致 MASH 患者静脉血栓栓塞事件增加的基本机制。
