Lower Ferritin Concentrations Are Associated with Decreased Hemolysis in Sickle Cell Disease Children without Iron Overload.

The role of iron in the pathophysiology of sickle cell disease (SCD) is complex and not fully understood. Iron overload is associated with disease severity primarily because multiple transfusions are linked to a severe SCD clinical course. Additionally, hemolysis, also associated with disease severity, increases iron absorption. Iron deficiency decreases red cell MCHC, which lowers Hb S polymerization and thus may improve the clinical manifestations of SCD. Such a hypothesis is supported by our recent observation of a homozygous SCD adult with iron deficiency anemia and a very low hemolytic rate that increased dramatically with iron supplementation. This experience and similar case reports from the literature led us to examine the relationship of ferritin levels with hemolysis and other laboratory and clinical parameters in a group of non-iron overloaded children with sickle cell disease. All subjects in this analysis were enrolled in a prospective study of the prevalence and significance of pulmonary hypertension in children with SCD (PUSH). Because of the known association of high serum ferritin with multiple transfusions and with a severe clinical course in this and other SCD populations, we excluded children who had ferritin concentrations of 242 ng/ml or higher. This cut-off value is 3 SDs above the geometric mean of the ferritin concentrations in a group of 42 age, sex, and ethnicity matched control children without SCD. Hence the group of sickle cell children with ferritin levels of < 242 ng/ml should include only those with iron deficiency or with normal iron stores. The table shows correlations between serum ferritin (natural log) and age, hematologic, iron status, and hemolytic parameters, including a previously described hemolytic component derived by principal component analysis from reticulocyte count, LDH, AST, and bilirubin.

In this group of non-iron overloaded SCD children and adolescents (median age 12 y, range 3–20 y), lower serum ferritin was related to higher serum transferrin and to lower serum iron and MCV, documenting that serum ferritin was reflective of iron status. Hemolytic parameters such as reticulocyte count and the hemolytic component were significantly lower with lower ferritin levels. In multivariable analysis these relationships remained statistically significant (P for MCV and ferritin: 0.003, P for hemolytic component and ferritin: 0.044) even after correcting for alpha-thalassemia, which is known to also lower MCV and hemolysis, and for markers of inflammation (WBC) and liver disease (ALT), which could increase the ferritin level regardless of iron stores. Ferritin was significantly lower in older subjects, probably as a result of growth-related red cell mass expansion in the presence of marginal iron stores. Our results thus suggest that low iron stores are independently associated with decreased hemolysis. Low hemolysis is likely to be beneficial in SCD by reducing hemolysis-related vasculopathy, which in adult SCD patients predicts an increased risk of pulmonary hypertension, leg ulcers, priapism, and death. Whether iron status per se plays a role in the pathogenesis of SCD vasculopathy is not known. In non-SCD adults, decreasing iron stores by frequent blood donation has beneficial effects on endothelial function and cardiovascular disease even within the normal range for iron stores. Hence, lowering iron stores could benefit SCD subjects by an additional, hemolysis-independent mechanism. Therapeutic iron depletion is not an option for children because of their need for adequate iron stores for optimal physical and neuro-psychological development. However, carefully controlled studies should be considered to reduce iron stores and so decrease the hemolytic rate in adults with SCD. It may be possible to achieve levels of iron reduction that lower hemolysis but do not worsen the anemia: in our study subjects, low iron stores were not associated with increased anemia and the red cell counts were actually higher with lower ferritin levels.

Gordeuk:TRF Pharma: Research Funding; Merck: Research Funding; Biomarin pharmaceutical company: Research Funding; Novartis: Speakers Bureau.