Effects of free iron on red cells from patients with either β-thalassemia or SCD. In pathologic red cells free iron sustains chronic oxidation with generation of reactive oxygen species (ROS) throughout the Fenton reaction. This requires an efficient antioxidant machinery with the metabolic support of ATP (see also Figure 3). The chronic and severe red cell membrane damage is further amplified respectively by membrane association of free alpha chains in β-thalassemic erythrocytes and cyclic polymerization/depolymerization events in sickle red cells. In both disorders, red cell membrane oxidation results in (1) increased membrane mechanical instability favoring to abnormally clusterization of oxidized band 3 (B3); (2) exposition of phosphatidyl serine (PS); and (3) generation of erythroid microparticles (E-MP), also carrying PS. The cumulative effects of oxidation are the premature red cell aging with accelerated removal by erythrophagocytosis mediated by both PS exposure and naturally occurring anti–band 3 antibody (N-Ab). In addition, in sickle erythrocytes, membrane damage is associated with increase permeability to Ca²⁺ with the activation of the Gardos channel (KCNN4) coupled with the oxidation induced activation of the K-Cl (KCC) cotransport. This ends in sickle red cell dehydration, relative increase in HbS concentration with a negative impact on HbS polymerization kinetic. Of note, in SCD a smaller component of hemolysis takes place intravascularly with saturation of physiologic binding proteins (eg, hemopexin) allowing for the presence of free heme and Hb in the peripheral circulation.