Enterohemorrhagic Escherichia coli (EHEC) causes thrombotic complications, yet the red blood cell (RBC)-centered mechanism has remained unclear. Although Shiga toxin (Stx) is regarded as the central virulence factor of EHEC, we identify the RTX-family hemolysin EhxA, not Stx2, as the driver of RBC-mediated thrombogenesis. EHEC infection induced Ca²⁺ influx, phosphatidylserine (PS) externalization, and a morphological progression from discocyte to echinocyte to spherocyte, accompanied by thrombin generation, RBC-endothelium adhesion, and RBC aggregation. Deletion of ehxA abolished these responses, genetic complementation restored them, and purified EhxA recapitulated them in bacteria-free assays while localizing to intact RBC membranes. By contrast, an isogenic Δstx2 mutant was indistinguishable from wild type, and purified Stx2 did not elicit PS exposure. Multiple linear regression identified PS exposure as the principal predictor linking morphology to procoagulant outputs. In rats, wild-type infection increased RBC remodeling and venous thrombosis, whereas ΔehxA did not. These findings define an EhxA-Ca²⁺-PS axis driving RBC structural remodeling and procoagulant activation during EHEC infection, paralleling the RtxA mechanism of Vibrio vulnificus, and nominate RTX toxins as therapeutic targets for preventing toxin-induced coagulopathies.