Oral iron and blood donation: cui bono?

Following development of the ferritin test four decades ago, investigators turned their attention to the iron status of blood donors^1,2. Scrutiny of donation-related iron depletion is motivated by concern for donor health and wellbeing, and also by the operational impact of deferral for low haemoglobin, which leads to donor loss and lowers the efficiency of blood collection. Despite unequivocal evidence that blood donation plays an important -though not exclusive- causal role in the onset or exacerbation of iron deficiency in blood donors, the resulting clinical implications remain poorly documented. Indeed, an expert advisory group convened by the AABB, which publishes standards and provides accreditation services for blood collectors in the United States, recently issued a report noting the limited evidence for adverse effects in blood donors from non-anemic iron depletion, with the exception of pica (compulsive craving and ingestion of non-food items)³. Two recent reviews and two national cohort studies reach similar conclusions^4–7.

Blood center and regulatory interest are evidenced by several large cohort studies and public funding to support them. The strength of measures optimally adopted to ameliorate donation-related iron depletion, however, might depend on the perceived seriousness of the risk(s) being averted for a given intervention. Any tightening up of donor eligibility criteria has a downstream impact on product availability, so documentation of the clinical impact of blood donation is of more than academic interest. International surveys show that few blood centers systematically measure blood donor iron status, while about half provide supplemental iron to their donors, generally on a targeted basis rather than systematically^8,9.

Against this backdrop, Pachikian et al. present results from an innovative trial assessing the impact of iron supplementation on biomarkers of iron status and iron homeostasis as well as physiological performance¹⁰. In their randomised, longitudinal study, forty-four moderately-trained, never-donor male subjects age 18 to 40 were tested before and after donation to assess numerous measures of haematologic and iron status and of physiological performance. Three of the four groups were assigned to donate a standard whole blood (WB) donation, repeated twice at 3-month intervals, while the fourth group gave sham donations. As subjects were blindfolded during the procedure, none knew whether their donation was real or simulated. The control group performing the simulated donation was assigned to placebo pills with no iron content, as was one of the three groups donating 470 mL of WB. The remaining two groups received pills with 20 or 80 mg elemental iron in the form of ferrous gluconate, with instructions to take one pill daily for 28 days following the donation procedure. The simulated donation and placebo pills provide strong protection against confounding of the associations between donation, biomarkers, and sport performance, as well as the impact of supplemental iron on those associations. Hence, assessments of the impact of donation on physiological endurance, and of the impact of exogenous iron on sport performance metrics are appropriately controlled. Measurements were taken 1 week prior to donation and afterwards at intervals of 2 days and 1, 2 and 4 weeks. The authors report, unsurprisingly, that donation has a measurable impact on red cell and iron biomarkers observable from the first donation and often progressing with serial donation. Less expected, they report that on the whole neither 20 nor 80 mg of iron for 28 days post-donation was sufficient to significantly alter the trajectory of iron status post-donation compared to the group taking no iron. In contrast, they report that both the lower and higher doses of iron blunt the deleterious impact of donation on physiological performance.

The detailed results provide an opportunity to parse out the evolution of iron status across storage, functional, and transport iron compartments separately, with differences reported by group, time, and a group-by-time interaction for 19 different measures of haematological or iron status and 8 measures of physiological function. Post hoc comparisons of group means are also provided for the 3 donation groups compared to the sham donation group, and for pairwise comparisons of iron dosage among subjects making authentic donations (0 vs 20 mg, 0 vs 80 mg, 20 vs 80 mg). The authors find that the recovery kinetics of haemoglobin mass and ferritin levels for 4 weeks post-donation do not differ across 0-, 20-, and 80-mg iron pill groups. In contrast, the decrease in hepcidin and increase in soluble transferrin receptor (sTfR) evolved differently depending on the iron content of pills. Recovery of hepcidin in those taking 80 mg of iron was comparable to that of the simulated donation group, while sTfR evolved differently for those taking 20 or 80 mg of iron. The authors conclude that some aspects of iron homeostasis and functional iron in the tissues were impacted by iron consumption post-donation.

Of the 8 measures of physiologic performance, maximal power output (P_max) and peak oxygen consumption (VO₂ peak) evolved equivalently between the 20 and 80 mg pill groups and the placebo group (simulated donation), but not between the placebo group and the WB donation group taking no iron. The authors suggest that supplemental iron of 20 mg or more protects against the impact of repeated donation on these two measures of fitness, which they hypothesise may be attributable to preservation of enzymatic activity in the mitochondria of skeletal muscle rather than related to oxygen transport capacity.

To whom do these results apply, and how well do they represent the overall donor population? The authors note the proper caution that the study participants were all iron-replete young men and that the observed results might differ in iron-deficient subjects. Quite likely these results apply to a fairly narrow segment of the donor pool in many countries, at least in terms of iron status at the point of donation. In Canada and the United States, an estimated 13–17% of blood donors have ferritin <12 ng/mL at the time of donation, and approximately 35–40% have ferritin <26 ng/mL^11–13. In Australia, 13.5% of a nationally-representative sample had ferritin <15 ng/mL, while routine testing over six years in Switzerland yielded 6.7% of males and 17.5% of females with ferritin <10 ng/mL^14,15. To be sure, the precipitous drop in ferritin seen over 3 donations in this study population with no prior donations mirrors the kinetics documented by Simon, et al. nearly 40 years ago² and more recently by Cable¹⁶. In fact, with starting ferritin values approximately 80–100 ng/mL prior to donation 1 and 30 ng/mL after the 3^rd donation, it could be inferred that the results correspond precisely to the population studied, novice male donors, and reasonably fit ones at that. That the impact of iron on recovery of iron biomarkers might indeed be stronger (as the authors postulate) for those with poor iron status is well-demonstrated by the REDS-III HEIRS study in the US. The primary results showed that donors receiving daily iron pills recovered haemoglobin uniformly quickly (within about a month), whereas two-thirds of donors randomised to no supplemental iron had not recovered their haemoglobin within 24 weeks¹⁷. A secondary analysis stratified by initial ferritin values found that oral iron impacted the recovery kinetics of many biomarkers of storage or red cell iron, and of iron homeostasis for those donors whose pre-donation ferritin values were <50 ng/mL¹⁸. The responsiveness of donor biomarkers to exogenous iron in HEIRS contrasts with the lack thereof in the current study, where all three donations were made with ferritin equal to or exceeding 50 ng/mL. While the risk for self-assessed symptoms relating to fatigue or quality of life at different levels of ferritin or other iron biomarkers remains poorly understood, the current study moves the field forward with respect to objective measures of physiological endurance. By demonstrating relative improvement in sport performance by oral iron ingestion post-donation, and at relatively robust levels of iron stores, the authors put some contours around how we understand the impact of donation on blood donors and, perhaps, even point to biological mechanisms for further investigation.

The phrase cui bono is a Latin term meaning “who benefits?”, often employed in a legal setting or criminal investigation where efforts to identify a responsible party focus on those who might benefit from a given event or outcome. Here, even while acknowledging that the study population is similar to a relatively small portion of the blood donor population, the implications for who might benefit from iron supplementation are intriguing. Whereas current practice in many jurisdictions is to recommend iron supplementation to “frequent” donors or those with low haemoglobin, this study suggests a benefit from exogenous iron even for iron-replete donors. Not all blood donors engage in high-intensity exercise, of course, but this study suggests greater consideration of an “iron replacement” paradigm for supplemental iron in lieu of the current “risk” paradigm, where iron is indicated only for those shown to have or considered at risk for iron depletion. An approach that by default facilitates oral iron post-donation unless contraindicated would imply that the answer to cui bono might be: omnes, or (just about) everyone.