Background: Extracellular vesicles are a valuable source of biomarkers and display the pathophysiological status of various diseases. In COVID-19, EVs are explored in several studies for their ability to reflect molecular changes caused by SARS-CoV-2 infection and impacts on disease progression. Methods: In this study, we used a label-free shotgun proteomics approach to identify and quantify any alterations in EVs proteins abundance in severe COVID-19 patients. We isolated plasma extracellular vesicles from healthy donors and patients with severe COVID-19 by size exclusion chromatography (SEC). Then, flow cytometry was performed to assess the origin of EVs and investigate the presence of circulating procoagulant EVs in COVID-19 patients. A total protein extraction was performed and samples were analyzed by nLC-MS/MS in a Q-Exactive HF-X. Finally, computational analyzes were applied to sign biological processes related to disease pathogenesis. Results: We report significant changes in the proteome of EVs from patients with severe COVID-19. Differently expressed proteins in the disease groups were associated with platelet degranulation, integrin cell surface interaction, and acute inflammatory response. Flow cytometry experiments indicated an increase in total circulating EVs and with TF-dependent procoagulant activity.