Superdonors Have Decreased Iron Stores but Can Repeatedly Donate Whole Blood through Use of Iron Supplements and Decreased Serum Hepcidin Concentration.
Authors: Mast Alan E. , Foster Tisha , Pinder Holly L. , Beczkiewicz Craig A. , Bellissimo Daniel B. , Murphy Anthony T. , Kovacevic Steve , Wroblewski Victor J. , Witcher Derrick R. 
Published: October 2019

Abstract
Examination of the low hematocrit (HCT) deferral rates in whole blood donors based on gender/menstrual status and donation intensity unexpectedly revealed that low HCT deferral rates level off and even begin to decrease in frequent donors (>8 donations in 2 years) suggesting that frequent blood donors are a self-selected population possessing either behavioral or biochemical characteristics that allow greater iron absorption than the general population. To define these characteristics, 138 donors (101 male, 37 female, 136 Caucasian) that had donated 13 times in a 2-year period (“superdonors”) completed a questionnaire and had a blood sample analyzed for ferritin, hepcidin and HFE and JAK-2 genotypes. Ferritin was 31.0±20.3 ug/L for males and 25.2±14.8 ug/L for females. Two-thirds of both men and women had ferritin below 30 ug/L indicating that most have reduced iron stores. Average ferritin was ∼15 ug/L higher in donors taking multiple vitamins with iron or iron supplements than in those who did not take them. Hepcidin is an iron regulatory hormone that negatively regulates intestinal iron absorption. Serum hepcidin levels were determined using a liquid chromatography tandem mass spectrometry assay. The normal serum hepcidin concentration using this assay is 8–11 ng/ml [Blood110:1048 (2007)]. Serum hepcidin was greatly decreased in superdonors (males 2.9±5.4 ng/ml; females 2.8±2.7 ng/ml) and 55 had no detectable hepcidin (<1 ng/ml), suggesting that superdonors absorb maximal amounts of intestinal iron. The C282Y mutation in the HFE gene has been linked to unregulated iron absorption and the development of hemochromatosis. This mutation was analyzed to determine if heterozygosity is present at greater than expected frequency in superdonors. It is present in 21 (15.2%) of the superdonors. This is higher than the reported frequency of 10–12% in Caucasians but did not reach statistical significance. The JAK-2 mutation is strongly associated with polycythemia vera and other myeloproliferative disorders. None of the superdonors had this mutation. In summary, superdonors are able to frequently donate whole blood with a lower than expected frequency of low HCT deferral despite having very low iron stores. Many, but not all, superdonors take either multiple vitamins with iron or an iron supplement that partially accounts for their ability to repeatedly meet the HCT requirement for whole blood donation. A key biochemical characteristic of superdonors that also contributes to their ability to repeatedly donate whole blood is greatly reduced serum hepcidin concentration that allows maximal intestinal iron absorption. Genetic analyses revealed that there is a trend towards an increased prevalence of heterozygosity for the C282Y mutation that may allow some superdonors to efficiently absorb intestinal iron and donate frequently without low HCT deferral, but no evidence for presence of the JAK-2 mutation indicating that undiagnosed polycythemia vera is not a common cause for successful repeated blood donation by superdonors.