Enterohemorrhagic Escherichia coli secrete Shiga toxin and lead to hemolytic uremic syndrome. Patients have high levels of circulating prothrombotic extracellular vesicles (EVs) that expose phosphatidylserine and tissue factor and transfer Shiga toxin from the circulation into the kidney. Annexin A5 (AnxA5) binds to phosphatidylserine, affecting membrane dynamics. This study investigated the effect of anxA5 on EV uptake by human and murine phagocytes and used a mouse model of EHEC infection to study the effect of anxA5 on disease and systemic EV levels. EVs derived from human whole blood or HeLa cells were more readily taken up by THP-1 cells or RAW264.7 cells when the EVs were coated with anxA5. EVs from HeLa cells incubated with RAW264.7 cells induced phosphatidylserine exposure on the cells, suggesting a mechanism by which anxA5-coated EVs can bind to phagocytes before uptake. Mice treated with anxA5 for six days after inoculation with E. coli O157:H7 showed a dose-dependent delay in the development of clinical disease. Treated mice had lower levels of EVs in the circulation. In the presence of anxA5, EVs are taken up by phagocytes and their systemic levels are lower, and, as EVs transfer Shiga toxin to the kidney, this could postpone disease development.