Transfusion of red cells from donors with hereditary haemochromatosis improve haemoglobin increments in patients.

One purpose of red cell transfusion is to increase the haemoglobin concentration in the patient's bloodstream.1 Transfusion of red cell units donated by individuals with hereditary haemochromatosis (HH) remains controversial. We collected red cell units from HH donors in a clinical trial, and compared post-transfusion haemoglobin increments in consecutive patients who received paired HH and non-HH red cell transfusions over a 1-year period. Hereditary haemochromatosis is a common inherited disorder of iron metabolism,2 treated by regular phlebotomy to prevent iron accumulation and organ damage.3 Blood removed by phlebotomy from HH donors can be used for allogeneic transfusion, depending on national regulations. In the face of current critical shortages of blood products,4 persons with HH can broaden our donor base and help address this public health crisis. In May 2016, the Food and Drug Administration (FDA) Code of Federal Regulations (CFR) removed the requirement of special labelling for blood components from HH therapeutic phlebotomies if the donor meets all eligibility criteria [21 CFR 630.15(a)(2)]. FDA also requires collectors to perform therapeutic phlebotomy without charge for all individuals with HH, if some HH units are used in the allogeneic blood supply. In 2022, large blood collectors such as the American Red Cross began accepting HH donors; but many centres still exclude these donors. We have been collecting HH red cells for allogeneic transfusions at the NIH Clinical Center since 2001. We and others have shown that their safety profile is comparable to regular non-HH red cells; no seroconversions for transfusion-transmissible microorganisms occurred among HH donors, and no bacterial contamination or septic transfusion reaction were associated with HH red cells.5, 6 After storage up to 6 weeks, HH red cells pass all FDA requirements.7 In this study, we further evaluate the transfusion efficacy of red cells collected from HH donors by measuring the haemoglobin increments in recipients. Individuals with molecularly confirmed diagnosis of HH were enrolled in an institutional review board (IRB)-approved clinical protocol NCT00007150, which entails written informed consent. Blood components were collected in compliance with all FDA criteria. We reviewed all transfusion events that involved HH red cell units collected between November 1st, 2020 and October 31st, 2021 at the NIH Clinical Center. We excluded red cell transfusions from the study based on criteria specified in Figure S1. To eliminate both interpersonal variables and changes in blood recipient's clinical status, we used transfusions of non-HH red cells as ‘matched controls’, if the involved red cell units were collected in-house and transfused to the same recipient prior to or after the HH red cell transfusions within the same hospital admission. A total of 102 matched transfusion event pairs were identified, which were transfused to 65 patients (Table S1). The Hb increment following transfusions of HH red cell units was 1.27 ± 0.63 g/dL (Figure 1A), significantly greater than that of non-HH units with 1.11 ± 0.51 g/dL (p = 0.008). Recipient Hb increment was weakly but significantly correlated with the donor's predonation Hb concentration (r = 0.197, p = 0.041). The volumes of the HH red cell units were larger by approximately 7 mL (307.09 ± 20.92 mL vs. 300.16 ± 20.58 mL), which was statistically significant and possibly caused by the greater haematocrit of donors with HH. We adjusted the Hb increments for the red cell volume transfused (detailed in supplement). After this adjustment (Figure 1B), the transfusion outcome measured by Hb increments was still significantly better for HH red cell unit transfusions (1.06 g/dL vs. 0.95 g/dL, p = 0.014). Donor factors are known to affect recipient responses to transfusion.8 We excluded possible confounding factors, such as differences in the Hb concentrations of recipients before transfusions, time intervals to CBC measurements, storage times at transfusion, or transfusion reactions (Table 1). HH donors were on average older, with male preponderance, and more often repeat donors (Table 1), which may all be common features of HH donors, and may likely contribute to improving haemoglobin increments in patients transfused with red cell units from HH donors. HH donors are known to have increased Hb concentration, haematocrit and MCHC compared to persons without HH.9 Donation frequencies could have impacted the donors' iron stores and erythropoiesis; however, among repeat donors, the donation intervals did not significantly differ between the 2 donor cohorts, particularly not between the donors with less than 120 days since last donation (Table 1). In the 1-year study period, the HH donor cohort had a significantly lower deferral rate and were rarely deferred for low Hb concentration, which was the most common reason among non-HH donors (Table S2). For the 3273 red cell transfusions at the hospital, 18 transfusion reactions were reported without a significant difference between HH and non-HH donor red cell units (Table S2). Blood donations from persons with HH have been resisted in some countries because of concerns about safety, operational difficulty or cost.10 While initiation of therapy for a new HH patient requires more frequent phlebotomy and more physician intervention and laboratory analysis than routine donors,11 community blood centres with suitable expertise in phlebotomy may be more suited to handling collections from HH donors in the maintenance phase of treatment than other clinical settings. Our results demonstrate that red cell units collected from HH donors improved Hb increments in patients more than units from non-HH donors did. This may be partially attributable to demographic differences and iron repletion in HH donors, who were less likely to be deferred for low Hb than their peers. These findings add to the existing body of literature to encourage a practice change: accepting blood donations from individuals with HH can improve transfusion outcomes of patients while enhancing blood availability. Tsung-Lin Tsai designed the study, collected and analysed the data, discussed the data, and drafted the original version of the manuscript. Leonard N. Chen designed the study and edited the manuscript. Ting-Lan Ma analysed the data. Cathy Conry-Cantilena edited the manuscript. Willy A. Flegel revised the analysis, discussed the data, and substantially edited the manuscript throughout. Kamille A. West-Mitchell supervised the HH donor protocol, discussed the data and edited the manuscript. All authors reviewed the final version of the manuscript. The authors gratefully acknowledge Dr. Susan F. Leitman for originally devising the hereditary haemochromatosis blood donor protocol and serving as principal investigator for 13 years until 2014. This work was supported by the Intramural Research Program of the NIH Clinical Center (Projects ZIA CL002107 and ZIC CL002128). The authors declare that they have no competing interests. HH donors were enrolled in an institutional review board (IRB)-approved clinical protocol. The recipient study was determined by the NIH IRB to constitute exempt human subjects research (submission IRB001512) per 45CFR 46.104(d)(4)(ii). HH donors provided written informed consent. The haemochromatosis donor study was registered at clinicaltrials.gov as NCT00007150. The opinions expressed in this review are those of the authors and do not necessarily represent the views or policies of the National Institutes of Health, the Department of Health and Human Services, or the U.S. Federal Government. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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