In this work, we demonstrated that following intravascular hemolysis Hb oxidation leads to the formation of hemichrome, metHb, covalently cross-linked Hb multimers, and free heme. We showed that PHZ-induced IVH triggers IL-1 production via the NLRP3 inflammasome activation. We demonstrated that covalently cross-linked Hb forms during the decomposition of transient ferrylHb the molecules we proposed to name as gmoxHb. We Identified gmoxHb as a potent pro-inflammatory Hb form which induced the active production of IL-1 in vivo and in vitro. We confirmed that NLRP3 deficiency confers a survival advantage to mice in PHZ-induced IVH via increased tolerance and improved tissue damage control mechanisms. Identification of RBC-derived DAMPs and understanding the signaling mechanisms involved in the pathophysiology might provide new approaches for the treatment of IVH-related pathological conditions.