Summary of differences in iron turnover in SCD triggered by transfusion. This scheme is devised by the authors and builds upon current understandings from work by us and others.^16,23,29  (A) Iron turnover in SCD in the absence of blood transfusion is shown. Arrows denote iron fluxes involved in RBC formation in the BM from plasma transferrin pool (Tf) and destruction in RES macrophages (black) or through intravascular hemolysis (grey). Intravascular hemolysis forms a significant proportion of iron turnover directed to liver via hemopexin and haptoglobin binding of heme and hemoglobin, respectively. These mechanisms are nearly always saturated in SCD with a large proportion of free Hb available for glomerular filtration and renal uptake (via megalin and cubulin) leading to renal iron redistribution and urinary loss. IE in SCD is small relative to TM and effective erythropoiesis in SCD, so that BM is less expanded and IE iron reflux smaller than in TM, whereas iron absorption from the gut is not as increased through suppression of hepcidin. Hepatocytes and RES have low iron stores despite high rate of iron entry (as heme, Hb, or RBC) due to unopposed iron exit via ferroportin secondary to low hepcidin⁵⁰  and to heme-dependent up-regulation of ferroportin transcription.³²  Hypoxia and high rate of erythropoiesis reduce hepcidin⁵¹  despite chronic inflammatory state,⁵²  leading to relative hepcidin deficiency (low hepcidin/ferritin ratios) that facilitates iron egress from RES and hepatocytes. Urinary loss may be greater than intestinal absorption, leading to iron deficiency in a high proportion of nontransfused SCD patients. (B) Iron turnover in a transfused SCD patient is shown. Replacement of sickle RBCs with transfused RBCs decreases intravascular hemolysis (grey) and hence decreases iron clearance through hemopexin and haptoglobin by the liver and leaves less free Hb available for kidney uptake and urinary loss. Erythropoiesis of sickle RBCs is also suppressed if that transfusion regime increases the Hb. A greater proportion of iron turnover is through extravascular RBC destruction, which is subsequently directed via Tf to BM and hepatocytes. Increased Hb values after transfusion decrease erythropoiesis and transferrin iron clearance in BM: a greater proportion of transferrin iron is directed to hepatocytes which store increased iron (shown in dark grey). RES iron is also increased by greater erythrophagocytosis of transfused RBCs and increased hepcidin synthesis in hepatocytes (less hypoxia and lower erythropoietic rate). Tf saturation increases relative to nontransfused SCD, but rarely to the levels seen in TM and typically without NTBI formation. Continued hemolysis of remaining sickle RBCs continues to route heme iron away from the erythrophagocytosis-transferrin circuit to hepatocyte and kidney so that Tf saturation does not increase as much as in nonhemolytic conditions despite reduced erythroid uptake.