FIG. 5.

Heme release from Hb. Pathogens, products associated with the activation of innate and adaptive immunity, changes in plasma pH and osmolarity, microvascular clotting, vasoconstriction, and molecules released in the context of tissue damage can act directly or indirectly to trigger varying levels of RBC lyses and concomitant Hb leakage into plasma. Upon release from RBC, Hb tetramers are dissociated into dimers favoring oxidation of their prosthetic heme groups and promoting heme release. The shear number of RBC (2–3×10¹³ in humans), their high Hb (3×10⁶ molecules/RBC), and heme (1.2×10⁷ molecules/RBC) content make that lysis of a small fraction of RBC not detectable by standard hematological analyzes can lead to the release of significant amount of heme into plasma. Presumably for this reason, Hb is the main source of free heme involved in the pathogenesis of immune-mediated inflammatory diseases, such as severe sepsis and malaria. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars