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. 2023 Apr 19;7(5):e878.
doi: 10.1097/HS9.0000000000000878. eCollection 2023 May.

Effect of Eculizumab on Iron Metabolism in Transfusion-independent Patients With Paroxysmal Nocturnal Hemoglobinuria

Charlotte C M Schaap  1   2 , Saskia E M Schols  1   2   3 , Frank W M B Preijers  4 , Emiel de Jonge  4 , Coby M M Laarakkers  3 , Joop H Jansen  4 , Nicole M A Blijlevens  1   2 , Dorine W Swinkels  3   5 , Saskia M C Langemeijer  1   2
Affiliations

Effect of Eculizumab on Iron Metabolism in Transfusion-independent Patients With Paroxysmal Nocturnal Hemoglobinuria

Charlotte C M Schaap et al. Hemasphere. .
No abstract available

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Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.
Iron parameters, and correlations between markers for intravascular and extravascular hemolysis and iron parameters in transfusion-independent PNH patients not treated with a complement inhibitor and PNH patients treated with eculizumab. (A) Serum ferritin and TSAT determined in transfusion-independent PNH patients not treated with a complement inhibitor and transfusion-independent PNH patients treated with eculizumab. Boxes show median and first and third quartiles. Whiskers extend to minimum and maximum values. Dashed lines represents the upper limits of reference ranges. In the graph depicting serum ferritin levels, the lower dashed line represents the upper limit of the reference range of ferritin for premenopausal women and the upper dashed line represents the upper limit of the reference range of ferritin for men and postmenopausal women. Statistical significant differences between groups are highlighted with bars and corresponding P-values, Mann-Whitney U test. (B) Serum hepcidin, hepcidin/ferritin ratio, and ERFE determined in transfusion-independent PNH patients not treated with a complement inhibitor and transfusion-independent PNH patients treated with eculizumab. Boxes show median and first and third quartiles. Whiskers extend to minimum and maximum values. Upper limits of reference ranges of hepcidin and hepcidin/ferritin ratios are not depicted here as these are outside the axis limits. Reference ranges of serum hepcidin levels are <0.5–13.0 nM, <0.5–16.5 nM, and <0.5–15.5 nM for premenopausal women, postmenopausal women, and men, respectively. Reference ranges of hepcidin/ferritin ratios are 3.2–176.4 pmol/μg, 9.6–150.9 pmol/μg, and 3.1–92.7 pmol/μg for premenopausal women, postmenopausal women, and men, respectively. For ERFE, no reference intervals are available yet. Median level of ERFE determined in 10 healthy controls is 0.8 ng/mL (range, 0.2–27.5). Statistical significant differences between groups are highlighted with bars and corresponding P-values, Mann-Whitney U test. (C) Correlation between absolute reticulocyte count and hepcidin/ferritin, and absolute reticulocyte count and ERFE in transfusion-independent PNH patients not treated with a complement inhibitor and transfusion-independent PNH patients treated with eculizumab. Two ERFE outliers (1 in the untreated group [ERFE = 43.3 ng/mL] and 1 in the treated group [ERFE = 102.9 ng/mL]) were excluded from the analysis. Spearman correlation coefficients are depicted in each graph with corresponding P-values. P-values <0.05 are considered to be significant. PNH = paroxysmal nocturnal hemoglobinuria; ERFE = erythroferrone; TSAT = transferrin saturation.
Figure 2.
Figure 2.
Conceptual model of iron regulation in transfusion-independent untreated and eculizumab-treated patients with PNH. (A) Intravascular hemolysis in untreated PNH patients leads to supressed serum hepcidin levels as a result of iron deficiency due to urinary iron loss from hemosiderinuria as well as increased ERFE production induced by enhanced erythropoiesis. Low serum hepcidin levels promote duodenal absorption and iron release from macrophages of the RES in order to increase the iron availability for erythropoiesis. (B) Once intravascular hemolysis is blocked by the complement-C5 inhibitor eculizumab, urinary iron loss is inhibited. However, patients develop a variable degree of extravascular hemolysis, caused by phagocytosis of complement-C3d-opsonized PNH erythrocytes in the RES, leading to iron sequestration in macrophages. Because of a persistent enhanced erythropoiesis, ERFE production is increased, resulting in serum hepcidin levels that remain low relative to ferritin levels. The combination of both a decline of renal iron loss and erythropoiesis-mediated suppressed hepcidin levels contribute to a positive net iron balance and subsequent progressive iron deposition in the RES in patients on eculizumab with ongoing extravascular hemolysis. Figure created with BioRender.com. PNH = paroxysmal nocturnal hemoglobinuria; ERFE = erythroferrone; RES = reticuloendothelial system.
See this image and copyright information in PMC

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