Enterohemorrhagic Escherichia coli (EHEC) causes severe thrombotic microangiopathies, traditionally attributed to Shiga toxin. However, the direct mechanisms underlying red blood cell (RBC)-driven procoagulant activity remain undefined. Here, we identify the RTX-family hemolysin EhxA as the principal driver of RBC-mediated thrombogenesis during EHEC infection. Using human and rat RBC models, we demonstrate that EhxA triggers intracellular calcium influx and subsequent phosphatidylserine (PS) externalization. This PS-anchored signaling quantitatively dictates a structural remodeling of RBCs from discocytes into echinocytes and spherocytes. Consequently, this transformation amplifies procoagulant outputs, including thrombin generation, RBC-endothelium adhesion, and RBC self-aggregation. Deletion of the ehxA gene abolished these pathogenic RBC responses, whereas genetic complementation and bacteria-free assays using purified EhxA restored them. Strikingly, isogenic stx2 mutants failed to elicit comparable RBC phenotypes, functionally uncoupling this prothrombotic pathway from Shiga toxin. Furthermore, in vivo rat models confirmed that wild-type EHEC infection exacerbates RBC structural remodeling and venous thrombosis, effects entirely absent in ehxA-mutant infected hosts. Collectively, these findings establish a novel EhxA-Ca²⁺-PS pathway orchestrating RBC disintegration and highlight RTX-family toxins as promising targets for preventing pathogen-induced coagulopathies.