The donation interval of 56 days requires extension to 180 days for whole blood donors to recover from changes in iron metabolism

To the editor:

Iron deficiency (ID) is a frequently seen adverse event in whole blood donors, ultimately leading to deferral for donation because of low hemoglobin (Hb) values.¹  In accordance with guidelines of regulatory agencies and to protect whole blood donors from developing ID and anemia, many blood establishments worldwide require a minimum interval of 56 days between 2 donations.^2,3  This interval is based on studies from the 1940s and 1950s, investigating recovery of (only) Hb,^4,5  but more recently, it was reported to be too short to prevent ID.^6,7  Because Hb falls short as a marker for nonanemic ID,^8,9  and to prevent blood donors from developing ID, there is a need for additional insights into the kinetics of red cell indices and iron parameters over time after blood donation. This may prove useful to assess the optimal donation interval and to select the parameter that is most suited to define personalized intervals.

Between March 2013 and April 2014, 24 “new” (defined as 1 or 2 donations before the start of the study) and 25 “regular” (>10 previous donations) male whole blood donors were randomly selected and included in the study (Table 1), and they were subsequently followed for 180 days after donating 500 mL blood (supplemental Figure 1, available on the Blood Web site). Recovery of Hb and iron parameters was tested for differences between new and regular donors in blood drawn at baseline (before donation) and at 9 time points after donation (8 hours and days 2, 4, 8, 15, 29, 57, 85, and 180). Furthermore, differences in iron absorption and erythrocyte iron incorporation between both donors groups were investigated with oral and intravenous stable iron isotopes, administered at day 8 and measured at day 29 in a subgroup of 31 donors (15 new, 16 regular), who consecutively agreed to participate. This study was approved by the Medical Ethical Committee Arnhem-Nijmegen in the Netherlands and the Ethical Advisory Council of Sanquin Blood Supply. All participants gave their written, informed consent.

In regular donors, Hb, ferritin, and hepcidin were lower, and erythropoietin (EPO) and soluble transferrin receptor (sTfR) were higher compared with new donors (Figure 1A) similar to observations in previous studies.^10-13  Iron absorption (17.0% and 21.9% of oral iron administered) and incorporation into erythrocytes (81.6% and 83.7% of intravenous iron) after donation were not statistically significantly different between new and regular donors, although the former tended to be higher in regular donors (supplemental Table 1). Interestingly, in the lower ferritin range, a trend was observed of higher iron absorption percentages for regular compared with new donors (supplemental Figure 2). Although, low numbers and high variation preclude any definitive conclusions, these data corroborate the concept of the regular donor group comprising (at least) some donors who more adequately absorb dietary iron with faster recovery from iron losses. This concept is in agreement with higher and lower prevalence of variants in HFE and TMPRSS6, respectively, in regular donors (supplemental Table 2), but needs further confirmation in larger studies.

Patterns of change in parameters over time after whole blood donation were similar for new and regular donors with an increase in EPO and decrease in Hb and hepcidin after day 2 followed by a decrease in ferritin and increase in reticulocytes, sTfR, and total iron binding capacity (TIBC) after day 4 (Figure 1A). At day 57, for only a few parameters (TIBC, Hb indices, iron, reticulocyte hemoglobin equivalent) >85% of both regular and new donors were back at predonation levels (Figure 1B; supplemental Tables 3 and 4). This percentage was particularly low for ferritin: only 25.0% of new donors and 32.0% of regular donors reached predonation levels. At day 85, >90% of donors were back at baseline levels for all parameters except for TSAT, hepcidin, sTfR-ferritin index, ferritin, and EPO, in both donor groups. At day 180, ferritin levels of all regular donors had returned to predonation levels compared with 82.6% of new donors. Importantly, for ferritin, increase in percentage of new donors that reached predonation levels was slower over time and lower at 180 days than in regular donors. This apparent faster recovery from iron losses in regular donors may be ascribed to their afore-suggested higher innate mean baseline intestinal absorption rates (for ferritin levels) in addition to previously described exponential increases in intestinal iron absorption with ferritin decreases in the low ferritin range.¹⁴  Our observations on change of iron parameters after blood donation add detailed kinetic data to the already established theory of recovery of blood losses: (1) fast Hb decrease because of dilution to replace losses in blood volume (day 0-4), followed by (2) hypoxia-induced EPO production (days 0-4), (3) increase in EPO-induced erythropoiesis and associated increase in sTfR (days 4-29) and reticulocytes (days 2-8), (4) hepcidin decrease (day 1-8) through both signaling of increased erythropoiesis to hepatocytes¹⁵  and decrease in body iron levels, and (5) ferritin decrease (days 1-29) through low-hepcidin induced release of stored iron into plasma. Altogether, these responses lead to increased erythropoiesis and iron availability for incorporation in newly synthesized erythrocytes, resulting in a return of Hb and iron parameters to baseline levels in time after blood donation.

In most previous studies, only recovery of Hb after blood loss was investigated and new and regular donors were not compared.^4,5  Recently, in the Recipient Epidemiology and Donor Evaluation Study–III (REDS-III) study involving fewer time points and iron parameters, investigators also observed a decrease of Hb and hepcidin and increase of reticulocyte count and EPO upon blood donation.¹⁶  Moreover, and similar to our observations, they found that (1) absolute hepcidin levels decreased more in high ferritin donors, whereas EPO increased more in those with low ferritin, indicating that erythropoietic response to severe blood loss varies with baseline iron stores, and (2) recovery to baseline ferritin levels in high ferritin donors was less complete.

Interestingly, at baseline, 92% of new and 64% of regular donors had ferritin levels above the cutoff of 30 µg/L for ID (supplemental Figure 3). However, despite several reports on association between ferritin levels and symptoms of ID in blood donors,^17-19  it remains uncertain below which exact ferritin level complaints of ID occur. Recommended cutoffs differ between guidelines of various authorities and vary from 12 to 40 and even 100 µg/L to identify (possible) ID in the general population.^20,21  Because these values are largely based on older studies in the absence of international standards,^22,23  they are not ideally suited to define evidence-based cutoff values.

In conclusion, we provide detailed insights into changes and recovery in iron homeostasis over time until 180 days after blood donation in both regular and new whole blood donors. We conclude that for the vast majority of male donors, the donation interval of 56 days is too short to recover from donation-induced reduction in body iron stores.

To stay on the safe side, we propose, as our expert opinion, that ferritin should be kept above 30 µg/L at all times. Based on our observations, this implies a baseline ferritin at each donation of at least 50 µg/L. Furthermore, we propose ferritin as the best parameter to assess personalized donation intervals because it (1) significantly decreases upon blood donation in the present study and (2) has been found to be associated with symptomatic ID in blood donors.^17,18  Alternatively, and in the absence of point-of-care ferritin platforms, development of ID in donors may be prevented by (1) prolongation of donation intervals to 180 days in all donors as suggested by both the current and the REDS-III study¹⁶  and/or (2) (low) dose iron supplementation.^24,25