Iron, iron everywhere but not enough to donate

“Iron is an essential nutrient required by every human cell.” So begins a chapter of a standard textbook of hematology.1 For the millions of people who donate blood, iron is an essential element that they lose with each donation (mean, 242 ± 17 mg for men and 217 ± 11 mg for women). After the donation there is a lag of 4 or 5 days before there is a change in plasma iron kinetics. Thereafter, plasma iron concentrations decrease and the clearance rate of iron from the plasma increases. Generally, iron stores are adequate between the first and second donations. After the second donation, however, an increase in iron absorption to sustain the increase of plasma iron turnover is required to maintain iron balance.2 Then, with adequate iron stores, men are generally able to maintain this balance, not become anemic, and donate three to four times a year. Even so, 8 percent of males with four or five donations per year and 19 percent of those who donate every 8 weeks will become iron deficient.3 These male donors will either continue to donate, often with Hb and/or Hct levels that meet FDA and/or AABB requirements, but are diagnostic of anemia by clinical standards, or the donors become deferred if their Hb and/or Hct levels drop below the 12.5 g or 38 percent requirement. Women have a greater problem. Postmenopausal women have no ongoing iron depletion but start with lower iron stores and thus more frequently become iron deficient after multiple donations. Between 17 and 28 percent of postmenopausal women will become iron deficient on a schedule of four to six donations per year. Iron deficiency is therefore a potential problem for all donors, but its major impact is on women who are having menstrual periods and undergoing childbirth. Unless they are taking iron supplementation regularly, even two donations per year are associated with a 28-percent incidence of iron deficiency.3 Thus, a workshop convened by a number of blood-banking organizations focused on maintaining iron balance in women blood donors of childbearing age.4 Although the problem of iron depletion has long been recognized, it was only quantitated accurately when serum ferritin analysis became available. In 1977, Finch et al.5 published a study on the impact of iron depletion suggesting that male donors, while depleting their iron stores, were able to donate 2 to 3 units per year without appreciable incidence of iron deficiency, whereas women could only donate half that amount. Our group at the University of New Mexico conducted a study of iron supplementation of menstruating women blood donors that was published in 1984.6 It showed that administration of 39 mg of elemental iron daily allowed women in this group to donate every 8 weeks without significant iron depletion. The lack of enthusiastic response to this study by supplementation of these blood donors is perhaps understandable given that the elemental iron was in the form of ferrous sulfate, which is associated with gastrointestinal side effects and poisoning in children who have access to the medication. Thus, a series of studies by Gordeuk et al.7,8 and Brittenham et al.9 published between 1987 and 1996 investigating use of carbonyl iron, which is not associated significantly with gastrointestinal side effects or at all with poisoning, was significant in giving us a practical basis to move ahead. Why then have blood centers so short of donations not begun offering iron supplementation on a regular basis to their donors who are women of childbearing age? Several reasons emerged. First, blood centers in general are reluctant to be in the position of giving out medication because they do not typically have a doctor-patient relationship with the donor, and this would be a new paradigm for dealing with donors in a blood center setting. Second, there is concern about missing underlying diseases that would make this practice inappropriate. One such disease would be hemochromatosis with potential aggravation of iron overload. A second would be some other form of anemia, such as gastrointestinal blood loss, that should be investigated by a physician. The latter would be masked by iron supplementation. Third, there has been a general sense that people actually might be healthier with lower iron stores, particularly with regard to atherosclerosis.10 Despite these concerns, the information presented at the workshop presents a compelling case for moving ahead with a program of iron supplementation of this group of blood donors. Not only would it address the issue of inadequate blood donations to meet patient needs by providing a new source of regular donors, but it would also ensure that we are not harming donors in this group by depleting their iron stores inappropriately. Iron deficiency is associated with symptoms and functional changes due to the critical role played by iron in human cell function.1 In addition, when the donors become anemic they are unable to donate, and the anemia may trigger a costly medical evaluation. A program of iron supplementation of donors, as noted in the workshop report,4 would require caution to ensure that donors are not being supplemented inappropriately. This could be solved through an informed consent that suggests that all donors who undertake the iron supplementation inform their primary care physician. One could even require an approval by their primary care physician before the second donation and a refill of the iron. In addition, the routine supplementation program, unless additional controls are instituted, should be stopped sometime between the ages of 40 and 50, when the risk of colon cancer begins to become significant and the problem of masking an underlying disease could result from the iron supplementation. Required approval by the donor's physician would allow any appropriate screening for hemochromatosis to take place. The conclusion to the workshop as reported is somewhat disappointing, in that it suggests that an iron replacement protocol should only be done on a demonstration basis with data collected and used to evaluate the cost and validity of a program. However, I would contend that the data already published are more than sufficient to show the practicality, safety, and effectiveness of such a program. Nevertheless, one could concede the appropriateness of a larger demonstration project before national implementation. In my view, this subject is important enough that such a program should be planned and implemented immediately with a 1 to 2 year time frame in order to ensure that we are moving forward toward this necessary change in the paradigm of blood collection. A key resource for the continued viability of the volunteer blood program is regular donations by committed donors, particularly those with blood groups O and B. Although platelet and plasma donations are necessary and useful supplements to any blood donation program, there is a continuing and significant need for whole-blood donation. The other components can be obtained at such donations as well. The impact of RBC substitutes currently awaiting FDA approval is unknown, but it seems likely that the demand for whole-blood donations will continue to grow with the aging of the population and with new therapies. To respond to this increasing need, some way must be found to afford all individuals who meet the ever more restrictive blood donation requirements an opportunity to donate regularly. Women blood donors of childbearing age simply cannot do so unless they are regularly supplemented with iron. The use of carbonyl iron for this purpose has been substantiated in terms of both safety and efficacy. It is disappointing that cost data were not gathered for the workshop so we could determine the cost effectiveness of such a program. However, given the cost of recruitment of new donors and the cost to the healthcare establishment of blood shortages, it seems highly likely that this would be a cost-effective alternative. One could only hope that there will be a more enthusiastic response to the development of these demonstration programs and that we will see the blood establishment move forward with new paradigms to meet the need for increased blood donations. This will clearly be required if we continue with increasing restrictions based on the reduction of even theoretic risks of transfusion.