Protective mechanisms against hemolysis-driven disease. Protection mechanisms against Hb and heme toxicity adopt a hierarchical organization to match a diversity of hemolytic scenario. Macrophage recruitment to the liver augments erythrophagocytic capacity (level 1). Haptoglobin captures cell-free Hb dimers in an irreversible complex, stabilizing the heme-pocket structure and preventing tissue-barrier translocation in blood vessels and kidneys by its size-exclusion mechanism (level 2). Ultimately, hemopexin selectively captures free heme released from HbFe(III), blocking oxidative reactions, TLR4 ligation, and heme partitioning into lipophilic compartments (level 3).