Ferritin-guided iron supplementation as a paradigm shift in blood donor care: advancing donor iron management through evidence-based supplementation

Regular blood donation represents an essential lifeline for healthcare systems worldwide, yet it inevitably depletes donors’ iron stores, with each 500 mL whole blood donation resulting in approximately 250 mg of iron loss (1). The landmark Ferritin-guided iron supplementation as an alternative or complement to prolonged blood donation intervals (FORTE) trial by Karregat and colleagues addresses a critical challenge in transfusion medicine: how to maintain donor health and optimize post-donation iron recovery without compromising blood supply availability (2).

Methodological excellence and clinical significance

The FORTE trial represents a substantial methodological advance over previous iron supplementation studies in blood donors. As we noted in our recent correspondence (3), this gold-standard randomized controlled trial successfully tackled several limitations highlighted in the 2014 Cochrane review on iron supplementation (4). The study’s comprehensive design evaluated not only different dosages (30 vs. 60 mg elemental iron) but also intake frequencies (daily vs. alternate days), while simultaneously assessing tolerability, adherence, health outcomes, and donor return rates. This multidimensional approach is unprecedented in donor iron management research (2).

The trial enrolled 830 donors with ferritin levels ≤30 µg/L across seven blood donation centers in the Netherlands between August 2021 and January 2023. The primary outcomes, including iron deficiency (<15 µg/L), low ferritin (15–30 µg/L), and low hemoglobin, were rigorously assessed at 56, 122, and 180 days post-donation. The results demonstrate compelling efficacy: at 56 days, all iron supplementation groups showed significantly lower odds of iron deficiency compared with placebo, with daily 60 mg supplementation proving most effective [odds ratio: 0.60; 95% confidence interval (CI): 0.55–0.66] (2).

The ferrous bisglycinate advantage: resolving the tolerability crisis

The FORTE trial’s most clinically significant finding relates to tolerability. Historical concerns about gastrointestinal side effects have hindered widespread adoption of iron supplementation programs, with the Cochrane review reporting adverse event rates of 29% (4). The FORTE trial’s use of ferrous bisglycinate—an iron formulation that minimizes residual iron in the intestine through chelation—dramatically reduced adverse events to merely 0.24% (2). This formulation prevents binding to dietary compounds that inhibit iron absorption, thereby enhancing fractional uptake while reducing colonic iron exposure that typically causes gastrointestinal discomfort (5-7).

The achieved adherence rate of 70–80% across all supplementation groups validates this approach and provides proof-of-concept for implementing iron supplementation programs without the tolerability barriers that plagued earlier efforts. Both capsule counts and mobile application tracking confirmed consistent compliance, challenging previous assumptions that iron supplementation would be poorly tolerated by blood donors (2).

Dosage, frequency, and the hepcidin question

The FORTE trial provides nuanced insights into optimal supplementation strategies. While previous research suggested that alternate-day dosing might improve absorption by allowing hepcidin levels to wane between doses (6,8,9), the FORTE results show that daily 60 mg supplementation achieved superior outcomes for iron deficiency and low ferritin. Daily 60 mg supplementation yielded the lowest odds ratios: 0.60 for iron deficiency and 0.52 for low ferritin, compared to 0.65 and 0.61 respectively for alternate-day 60 mg dosing (2).

These findings suggest that the cumulative total iron dose may outweigh theoretical advantages of alternate-day dosing in this population. However, the observation that 60 mg alternate-day supplementation outperformed 30 mg daily supplementation—despite identical total iron delivery—indicates that higher absolute doses per intake may enhance fractional absorption, consistent with non-linear dose-response relationships in iron metabolism.

The effectiveness was particularly pronounced in female donors, showing stronger effect modification by sex (P for interaction <0.10) (2), which aligns with the higher baseline prevalence of iron deficiency in this population and suggests that iron supplementation could be especially beneficial for maintaining female donor health and retention.

Strategic implications: supplementation vs. extended intervals

The FORTE trial positions ferritin-guided iron supplementation as a viable alternative or complement to extended donation intervals. The Ferritin-guided Donation Intervals in whole-blood donors in the Netherlands (FIND'EM) trial previously demonstrated that ferritin-guided donation intervals significantly reduced iron deficiency but negatively impacted donor availability and return rates (10). In contrast, FORTE’s intention-to-return assessments showed similar rates between iron supplementation groups and placebo, while post-hoc analysis revealed that 88–95% of participants returned for donation by March 2025 (2)—a donor retention profile superior to extended-interval strategies (10).

This finding has profound implications for blood supply sustainability (11). By enabling donors to maintain standard donation intervals while preserving iron storage, supplementation programs could mitigate the supply constraints created by ferritin-based deferrals. The economic analysis comparing costs of supplementation programs vs. extended intervals and potential donor loss merits urgent attention from blood collection agencies worldwide.

Addressing selection bias and real-world implementation

Despite the trial’s methodological rigor, important limitations warrant discussion. Of 15,776 eligible donors invited, only 830 (5.3%) were randomized, with 83.1% declining participation. As the authors acknowledge, participants “were likely to have had some degree of openness towards iron supplements” (2), potentially inflating adherence rates compared with real-world implementation. This selection bias needs to be taken into account when considering mandatory or routine iron supplementation programs (3).

Furthermore, the study population was relatively homogeneous (95% Dutch origin), limiting generalizability across diverse populations with varying dietary iron intake, genetic factors affecting iron metabolism, and cultural attitudes toward supplementation.

Global perspectives and implementation barriers

Beyond the clinical evidence, ferritin-guided iron supplementation faces substantial jurisdiction-specific implementation barriers. Regulatory frameworks vary substantially across countries. In Japan, for example, the Japanese Red Cross blood services operate under legal mandates restricted to blood collection, testing, processing, and product distribution—not clinical diagnosis or therapeutic treatment requiring prescription. This precludes the streamlined supplementation pathway demonstrated in FORTE and necessitates different implementation models, such as provision of iron supplements or collaboration with primary care physicians (3).

An additional fundamental barrier is the cost and operational feasibility of ferritin measurement itself. While automated immunoassays for ferritin are widely available in high-income countries, the per-test cost (ranging from $10–30 US dollars depending on platform and volume) and laboratory infrastructure requirements may be prohibitive for blood establishments in resource-limited settings. Alternative strategies such as point-of-care ferritin testing or selective screening protocols (e.g., testing only high-risk groups such as frequent female donors) might improve cost-effectiveness, though validation studies are needed. In settings where universal ferritin screening is unfeasible, risk-based supplementation approaches—targeting donors with multiple donations within the past year or those with previous low hemoglobin deferral—could provide a pragmatic alternative, albeit with reduced precision compared to ferritin-guided strategies.

Cultural and educational factors also compound these barriers. Health literacy challenges have been documented among university students in Japan (12), and iron awareness remains relatively low among young women—a population particularly vulnerable to donation-induced iron deficiency (13). Recent data from the Japanese Red Cross indicate that approximately one-third of female first-time donors are already iron-deficient before their initial donation (14), underscoring the urgency of intervention but also the magnitude of the educational challenge.

Key implementation questions remain: (I) Will commercially available iron supplements contain sufficient elemental iron in appropriate formulations (particularly ferrous bisglycinate) to replicate FORTE’s results? (II) Should each country conduct population-specific validation studies on the acceptability of iron prescription or iron supplement provision by blood services, or can international evidence guide local policy? (III) How can blood services engage donors who are unaware of their iron status or resistant to supplementation?

Future directions and research priorities

The FORTE trial opens several critical research avenues that warrant further investigation. First, long-term follow-up beyond 180 days would clarify two key questions: Do supplementation effects persist across multiple donation cycles? Do cumulative benefits accrue for frequent donors? Second, cost-effectiveness analyses comparing supplementation programs against alternative strategies (extended intervals, dietary counseling, combined approaches) are essential for resource allocation decisions. Third, studies in diverse populations—including donors with different baseline iron status, dietary patterns, sex-based differences, and genetic variants affecting iron metabolism—would establish the generalizability of FORTE’s findings.

Additionally, investigation of optimal supplementation duration is needed. FORTE prescribed 56 days of supplementation following a single donation (2), but would shorter courses (e.g., 28 days) suffice for donors with less severe depletion? Could supplementation be titrated based on baseline ferritin levels, with higher-dose or longer-duration protocols reserved for donors with ferritin <15 µg/L? Such personalized approaches might optimize efficiency while maintaining effectiveness.

The potential role of supplementation in special donor populations also warrants study. Adolescent and young adult donors, frequent apheresis donors, and donors with heavy menstrual bleeding may benefit from tailored supplementation protocols. Similarly, investigation of whether prophylactic supplementation (initiated before donation-induced depletion occurs) could prevent iron deficiency more effectively than reactive supplementation merits evaluation.

Precision medicine in transfusion services

The ferritin-guided supplementation strategy exemplified by FORTE represents a shift toward precision medicine in donor care. By identifying at-risk donors through ferritin monitoring and providing targeted intervention with evidence-based protocols, blood services can move beyond one-size-fits-all deferral policies toward individualized donor management. This approach aligns with broader trends in healthcare toward biomarker-guided therapeutics and personalized risk stratification.

Moreover, integration of supplementation programs with electronic donor management systems could enable automated identification of eligible donors, personalized supplementation prescriptions based on individual iron trajectories, and longitudinal monitoring of intervention effectiveness. Such data-driven approaches could continuously refine supplementation protocols and identify donors requiring additional support.

Conclusions

The FORTE trial provides compelling evidence for ferritin-guided iron supplementation in blood donors with low iron storage (ferritin ≤30 µg/L). Daily 60 mg ferrous bisglycinate effectively prevented iron deficiency, restored ferritin levels, and maintained hemoglobin, with minimal side effects and excellent adherence (2). These findings establish iron supplementation as a viable alternative or complement to extended donation intervals for managing donor iron status.

However, translating this evidence into practice requires addressing jurisdiction-specific regulatory frameworks, cultural contexts, and healthcare system structures. For countries with favorable regulatory environments, FORTE provides a ready-made implementation blueprint. For others, creative solutions involving collaboration between blood services and primary care, public health education campaigns, and potentially regulatory reforms may be necessary.

As blood demand rises globally amid demographic aging and expanding clinical indications for transfusion (11), while donor demographics deteriorate and eligibility criteria tighten, optimizing donor health and retention becomes increasingly critical. The FORTE trial demonstrates that evidence-based iron supplementation can contribute meaningfully to this goal—protecting donor health, enhancing donor experience, and supporting sustainable blood supply. The challenge now lies in translating scientific excellence into operational reality across diverse healthcare contexts worldwide.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Blood. The article has undergone external peer review.

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-47/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-47/coif). N.H.T. serves as an unpaid editorial board member of Annals of Blood from March 2024 to February 2026. T.S. serves as a special appointed director of the Japanese Society of Transfusion Medicine and Cell Therapy. N.H.T. is an employee of the Japanese Red Cross Society and serves as a regional director for the Western Pacific region of the International Society of Blood Transfusion. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Kiss JE, Vassallo RR. How do we manage iron deficiency after blood donation? Br J Haematol 2018;181:590-603. [Crossref] [PubMed]
2. Karregat JHM, Meulenbeld A, Quee FA, et al. Ferritin-guided iron supplementation as an alternative or complement to prolonged blood donation intervals (FORTE): a double-blind, randomised, controlled trial. Lancet Haematol 2025;12:e694-704. [Crossref] [PubMed]
3. Sato T, Ikuta K, Odajima T, et al. Ferritin-guided iron supplementation in blood donors. Lancet Haematol 2025;12:e928. [Crossref] [PubMed]
4. Smith GA, Fisher SA, Doree C, et al. Oral or parenteral iron supplementation to reduce deferral, iron deficiency and/or anaemia in blood donors. Cochrane Database Syst Rev 2014;2014:CD009532. [Crossref] [PubMed]
5. Tolkien Z, Stecher L, Mander AP, et al. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One 2015;10:e0117383. [Crossref] [PubMed]
6. Ganz T. Systemic iron homeostasis. Physiol Rev 2013;93:1721-41. [Crossref] [PubMed]
7. Fischer JAJ, Cherian AM, Bone JN, et al. The effects of oral ferrous bisglycinate supplementation on hemoglobin and ferritin concentrations in adults and children: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev 2023;81:904-20. [Crossref] [PubMed]
8. Stoffel NU, Cercamondi CI, Brittenham G, et al. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol 2017;4:e524-33. [Crossref] [PubMed]
9. Kiss JE, Brambilla D, Glynn SA, et al. Oral iron supplementation after blood donation: a randomized clinical trial. JAMA 2015;313:575-83. [Crossref] [PubMed]
10. Meulenbeld A, Ramondt S, Sweegers MG, et al. Effectiveness of ferritin-guided donation intervals in whole-blood donors in the Netherlands (FIND'EM): a stepped-wedge cluster-randomised trial. Lancet 2024;404:31-43. [Crossref] [PubMed]
11. Raykar NP, Makin J, Khajanchi M, et al. Assessing the global burden of hemorrhage: The global blood supply, deficits, and potential solutions. SAGE Open Med 2021;9:20503121211054995. [Crossref] [PubMed]
12. Adeoya AA. Exploring health literacy among Japanese and international university students in Japan: A comparative cross-sectional study. J Migr Health 2025;11:100334. [Crossref] [PubMed]
13. Nakayama K, Osaka W, Togari T, et al. Comprehensive health literacy in Japan is lower than in Europe: a validated Japanese-language assessment of health literacy. BMC Public Health 2015;15:505. [Crossref] [PubMed]
14. Odajima T, Tsuno NH, Ishimaru F, et al. Iron deficiency among Japanese whole-blood donors measured by serum ferritin. Vox Sang 2024;119:912-20. [Crossref] [PubMed]