Adenoviral vector vaccines were central to COVID-19 control, yet postmarketing surveillance revealed a venous-predominant thrombotic signal, notably cerebral venous thrombosis, that platelet- and PF4-centric mechanisms do not fully explain. Reframing red blood cells (RBCs) as active contributors rather than passive bystanders, we tested an RBC-associated hypothesis using an adenovirus type 5 (Ad5) vector, rAd/HA(PR8), in rats within a predefined sub-hemolytic window (<10% hemolysis). Four hours after intravenous exposure, ex vivo RBCs showed increased surface phosphatidylserine (PS) exposure, a morphological progression from discocyte to echinocyte to spherocyte by scanning electron microscopy, and elevated microvesicle generation, together indicating a procoagulant shift. Whole-blood thrombin generation rose dose-dependently (10⁸-10⁹ OPU/Rat), and an in vivo inferior vena cava model showed a dose-responsive rise in thrombus burden. These readouts across scales are consistent with RBC involvement in adenoviral vector-linked venous thrombogenesis, offering a biologically plausible bridge to the venous-predominant epidemiology of the vaccination era without implying inter-species or product equivalence. Incorporating RBC-focused endpoints, such as PS exposure, morphology indices, microvesicle counts, and thrombin generation, into preclinical and early clinical screening may complement platelet-centric assessment and inform vector design.