Lower Ferritin Concentrations in Children with Sickle Cell Disease Are Associated with Decreased Hemolysis and Lower Tricuspid Regurgitant Velocity
Authors: Castro Oswaldo , Minniti Caterina , Niu Xiaomei , Nouraie Mehdi , Sable Craig , Dham Niti , Rana Sohail R , Campbell Andrew , Ensing Gregory , Kato Gregory J. , Gladwin Mark T. , Gordeuk Victor R. 
Published: April 2020

Abstract
Considerable evidence suggests that hemolysis may be a cause of vasculopathy in sickle cell disease (SCD) and be associated with pulmonary hypertension risk in both adult and pediatric SCD patients. We recently treated an SCD adult for iron deficiency. Reticulocytes, LDH, and AST were normal or near normal before iron treatment but increased markedly with iron supplementation without a commensurate increase in the hemoglobin concentration. This and similar cases in the literature suggest that iron deficiency decreases hemolysis in SCD. To test this hypothesis we examined the association of serum ferritin concentration with hemolytic parameters and tricuspid regurgitant jet velocity (TRV) in 234 SCD children enrolled in a prospective multi-center study of the prevalence and significance of pulmonary hypertension. All studies were done in children who were outpatients and in the steady state of their disease. There were 32 children with ferritin concentrations &lt; 50 ng/ml and 202 with ferritins of 50 ng/ml or higher. We chose the &lt; 50 ng/ml ferritin cut off value because it would be expected to include both patients with iron deficiency whose serum ferritin concentration was in the deficient range and those whose ferritin was in the low normal range as a result of sickle-related inflammation. The table shows that patients in the lower ferritin group were older and had lower MCV, fewer transfusions, lower hemolytic markers (including a hemolytic index generated by principal component analysis of LDH, AST, total bilirubin and reticulocytes), and a trend to less severe anemia. The differences remained after adjustment for the number of blood transfusions.
Comparison of children with SCD at steady state according to serum ferritin concentration. Results in mean or geometric mean and 95% confidence interval unless otherwise stated.
Ferritin &lt;50 N= 32 Ferritin 50 + N=202 P value P value (Adjusted for # transfusions) Age, y 13.6 (12.3–14.9) 11.7 (11.0–12.4) 0.039 0.002 Female, N (%) 14 (44) 96 (48) 0.69 0.59 SC and Sb+-Thal, N (%) 12 (37) 45 (23) 0.08 0.26 &gt; 4 blood Tx, N (%) 3 (10) 67 (34) 0.011 - Interleukin-6 ng/ml 0.5 (0.3–1.2) 0.6 (0.5–0.8) 0.6 0.6 TRV, m/sec 2.17 (2.05–2.29) 2.28 (2.24–2.32) 0.033 0.020 Hemoglobin, g/dl 9.7 (9.0–10.5) 9.3 (9.0–9.5) 0.20 0.16 MCV, fl 77.4 (73.0–81.8) 85.9 (84.4–87.5) 0.0001 0.0008 Reticulocytes (×103/mm3) 166 (137–202) 208 (188–229) 0.022 0.06 Tot. Bilirubin (mg/dl) 1.7 (1.3–2.2) 2.3 (2.1–2.5) 0.029 0.051 LDH (mU/ml) 342 (284–411) 386 (364–410) 0.14 0.11 AST (mU/ml) 35 (29–42) 40 (38–42) 0.09 0.046 Hemolytic index −0.6 (−1.2–0.1) 0.1 (−0.1–0.4) 0.018 0.023
Plasma interleukin-6 concentrations were not different between the two groups suggesting that the differences in TRV and hemolyis were not due to increased inflammation in the high ferritin group. To further account for the effect of multiple transfusions on ferritin level we also analyzed patients who had fewer than 5 blood transfusions in their lifetime. Twenty-six patients with &lt; 5 transfusions and ferritin &lt; 50 ng/ml were significantly older (13.5 vs 10.5 y, P=0.004), tended to have higher Hb level (10.1 vs 9.4 g/dl, P=0.08) and had lower TRV (2.15 vs 2.29 m/s, P=0.017), MCV (77 vs 84 fl, P=0.008), and hemolytic index (−0.8 vs −0.1, P=0.028) than 131 of their counterparts who had ferritin of 50 ng/ml or higher. These results suggest that incipient or latent iron deficiency may develop as SCD children grow to early adolescence and be associated with lower hemolytic rate and TRV without a noticeable adverse effect on their anemia.