Iron Status Is Inversely Correlated with Circulating Red Cells in Patients with Sickle Cell Anemia

Introduction: Sickle cell anemia (SCA, HbSS) arises from the presence of sickle hemoglobin (HbS, a consequence of a single base mutation in HBB gene). Upon deoxygenation, deoxy-HbS polymerizes with detrimental effects on shape, function, and lifespan of the erythrocytes. Because the delay time of sickling is inversely proportional to the mean cellular hemoglobin concentration (MCHC), decreasing the concentration of HbS is an attractive therapeutic approach. We recently demonstrated that dietary iron restriction decreases MCHC with a concomitant improvement in hematologic parameters and a decreased propensity to sickle in the Townes murine model of sickle cell anemia. Data describing the relationship between iron status, MCHC, and hematologic parameters in SCA patients are limited to isolated case series that do not account for alpha thalassemia, a known modifier of SCA severity. Based on our observations in mice, we hypothesize that decreased iron availability is associated with improved hematologic parameters in SCA patients in the absence of alpha thalassemia. We investigated the relationship between MCHC and red cell count, as well as transferrin saturation and red cell count, in healthy volunteers and sickle cell patients without alpha thalassemia.

Methods: A database consisting of 795 patients with sickle cell disease (all genotypes) attending the National Institutes of Health between 2001 and 2015 was queried (see table). Data were filtered for sickle genotype, whether on hydroxyurea therapy, transfusion status (HbA), alpha thalassemia genotype, and relevant hematologic and/or iron panels obtained on the same visit. Data from healthy volunteers were obtained from the National Institutes of Health Biomedical Translational Research Information System (BTRIS) database filtering for those without detectable HbS that had hematologic and iron panel data obtained on the same visit. Correlations were analyzed by the Pearson correlation coefficient, r. p-values < 0.05 were considered statistically significant.

Results: Analyses were performed on patients with HbSS without detectable HbA that were not taking hydroxyurea and did not have alpha thalassemia. Thirty-nine of these patients had MCHC and red cell counts obtained on the same visit. Data indicate that MCHC is inversely correlated with red cell count in these patients (r=-0.423; p = 0.007). Importantly, no significant relationship between MCHC and red cell count was observed in healthy volunteers (n=40; r=-0.125; p =0.438). Transferrin saturation is directly correlated with circulating red cells in healthy volunteers (n=65; r=0.359; p=0.0033). However, in patients with sickle cell disease transferrin saturation has an inverse relationship with red cell count (n=53; r=-0.3131; p=0.0225).

Conclusions: Transferrin saturation and MCHC have are inversely correlated with circulating red cell counts in patients with sickle cell disease. These results support the concept that decreased iron availability improves hematologic parameters in sickle cell disease. Future studies will focus on pharmacologic means to achieve this end.

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