Extracellular Vesicles Reflect Thrombo‐Inflammatory, Endothelial and Tissue‐Remodelling Changes in Cirrhosis

Background and aims: Cirrhosis is characterized by progressive immune dysregulation, endothelial dysfunction, and haemostatic imbalance. Circulating extracellular vesicles (EVs) have emerged as potential biomarkers reflecting these pathophysiological processes. We aimed to determine whether EVs mirror disease severity and predict liver-related outcomes in cirrhosis. Methods: In this prospective single-centre study, patients with compensated, stable decompensated, or acutely decompensated cirrhosis were enrolled. EVs were isolated from platelet-poor plasma and quantified by flow cytometry to characterize platelet-, endothelial-, immune-, and CK18+ EVs, EVs expressing markers associated with endothelial anticoagulant pathways and tissue remodelling. Primary endpoints were first hepatic decompensation in compensated cirrhosis and a composite of further decompensation, acute-on-chronic liver failure, or liver-related mortality in acutely decompensated cirrhosis. Associations were analysed using Fine-Grey competing-risk models. Results: We included 228 patients, including 75 compensated, 44 stable decompensated, and 109 acutely decompensated. Median follow-up was 418 days. EV profiling showed progressive increases in total, platelet-derived, endothelial-, immune-derived, and tissue remodelling-associated EVs across Child-Pugh stages, suggestive of increasing thrombo-inflammatory and endothelial perturbation. First hepatic decompensation occurred in 7 patients with compensated cirrhosis and was associated with higher MELD and Child-Pugh scores, alcohol-related aetiology, and lower platelet count. In univariate competing-risk analyses, higher levels of several EV subpopulations were associated with first decompensation, but these associations disappeared after adjustment for MELD. Among patients with decompensated cirrhosis, 65 developed further decompensation, ACLF, or liver-related death; higher CRP levels were associated with these events, whereas no EV subpopulation was associated with the composite outcome. Conclusions: Circulating EVs reflect cirrhosis severity and are suggestive of progressive thrombo-inflammatory, endothelial, and tissue-remodelling changes. However, EVs were not independently associated with clinical outcomes.