Transfusion-acquired transient hemoglobinopathies: a case report and review of the literature

Introduction

Transfusion-acquired hemoglobinopathies occur when asymptomatic blood donors introduce red blood cells (RBCs) containing abnormal hemoglobin variants to recipients. The literature extensively discusses diagnostic challenges associated with transfusion-acquired hemoglobinopathies; however, the clinical significance of such transfusions remains unclear. While hemoglobin S (HbS) is the most commonly reported variant implicated in acquired hemoglobinopathies, numerous other hemoglobin variants have also been encountered in this context (1-5). Screening for non-HbS hemoglobinopathies is not routinely conducted during blood donation. Certain hemoglobinopathies can be asymptomatic with mild or no anemia, even in homozygous individuals. The severity of symptoms and degree of anemia can vary depending on the specific hemoglobinopathy. Since 2016 the US Food and Drug Administration (FDA) has mandated minimum hemoglobin and hematocrit levels for blood donation. Male allogeneic donors with a hemoglobin below 13.0 g/dL or a hematocrit below 39%, and female donors with a hemoglobin below 12.0–12.5 g/dL or a hematocrit below 36–38% have been precluded from donation (6,7). The absence of targeted hemoglobinopathy screening during blood donation permits some asymptomatic individuals with hemoglobinopathies to donate (3). The FDA-mandated minimums make transfusion-acquired hemoglobinopathies involving homozygous donors much less likely, with no such cases having been reported in the literature.

Hemoglobin C trait (HbAC) and hemoglobin C disease (HbCC) are typically asymptomatic with mild or no hemolytic anemia. Approximately 2–3% of African Americans, and greater than 15% of individuals in some West African populations, have at least one hemoglobin C allele, with an estimated 1 in 6,000 having HbCC (8,9). Patients with HbC and concurrent β⁰ thalassemia typically present with severe hemolytic anemia, and would be unlikely to meet donation requirements. Unlike HbS, crystals of HbC melt under low oxygen conditions and do not cause vaso-occlusion. In HbC patients, RBCs are more rigid and prone to being trapped and destroyed in the spleen resulting in reduced survival (9,10). We present a compelling case highlighting the apparent acquisition of a hemoglobin C variant from an asymptomatic blood donor, the first report of an acquired hemoglobinopathy from a presumed homozygous donor. We present this article in accordance with the CARE reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-2026-1-0004/rc).

Case presentation

A 46-year-old man with sickle cell disease (HbSS) regularly scheduled for RBC exchange every 5–6 weeks for secondary stroke prevention underwent routine RBC replacement, receiving four units. Therapeutic targets post procedure are HbS less than 30%, and hematocrit between 28–30%. The recipient tolerated the procedure well. Post-procedure capillary zone electrophoresis (CZE) used to monitor therapeutic transfusion efficacy, performed on a Capillarys-3 Octa (Sebia, Lisses, France), revealed an HbC fraction of 8% suggesting an acquired hemoglobinopathy (Table 1). Segments from each unit of transfused RBCs were tested using CZE, revealing that 1 unit contained 97% of a hemoglobin variant migrating in the C fraction. Over the following 44 days, the recipient’s hemoglobin C fraction decreased to 0.0%, without additional RBC exchanges or transfusions during this time. CZE findings for the recipient and donor are presented in Table 1 and Figure 1, respectively. No significant changes in post-procedure hematological parameters were observed (Table 2).

Figure 1 Capillary zone electrophoresis hemoglobin profile of donor red blood cell unit showing predominant (97%) HbC fraction. HbC, hemoglobin C.

Follow up investigation by the blood supplier revealed the blood donor was a 38-year-old man who had undergone RBC donation on nine separate occasions. The implicated RBC unit in this case was collected from whole blood. Two prior attempts at apheresis-based RBC collection in this donor had been unsuccessful, one due to clogging of the apheresis filter and the other due to unspecified quality control issues. Multiple Sickledex sickle cell screening assays (Streck, La Vista, NE, USA) for HbS performed by the blood supplier on the donor’s blood were negative. The donor denied knowledge of any blood diseases, and his hemoglobin level prior to his most recent collection was 13.8 g/dL. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Publication of this case report and accompanying images was waived from patient consent according to the University of Miami Institutional Review Board (approval No. 20201331).

Discussion

To the best of our knowledge, this is the first report of a transfusion-acquired hemoglobinopathy from a donor who is apparently homozygous for HbCC. Individuals with HbC disease can present with normal Hb or with mild chronic hemolytic anemia, having Hb ranging from within the normal reference interval down to 8 g/dL (11). RBCs for HbC individuals are microcytic with an average mean corpuscular volume (MCV) of 55 fL (12). The mean corpuscular hemoglobin concentration (MCHC) can be high or at the top of normal range. The interaction of HbC with the cell membrane cation transporter makes the cell smaller, less deformable and more likely to undergo extravascular hemolysis in the spleen. Severity of anemia and symptoms increase if HbC is co-inherited with β thalassemia. Analysis of the present case is limited based on available results, but given that our blood donor’s hemoglobin exceeded the FDA’s mandated threshold for donation, and no history of blood donation deferrals due to low hemoglobin or hematocrit, certain variants are less likely. Further workup would still be required in order to definitively identify the donor’s specific hemoglobinopathy as multiple variants, such as Hb O-Arab, could yield similar CZE findings.

Current World Health Organization (WHO) guidelines do not provide recommendations for hemoglobinopathy screening in blood donors (13). Universal screening of donors for hemoglobinopathies would create a significant financial burden, with the utility and necessity of such testing not being well established. Prevalence of hemoglobinopathies in the donor population is one key consideration to justify screening, with one study from Ghana demonstrating that out of 150 donors tested, approximately 11% were sickle cell trait carriers (HbAS) testing positive for sickling by the sodium metabisulphite method (14). Given regional differences in the population of donors, and variability of blood donor screening practices among different countries, the degree and impact of transfusion-acquired hemoglobinopathies may vary considerably.

In addition to donor population prevalence, screening RBCs for hemoglobinopathies may also be indicated in cases where collection issues involving filtration or quality control occur, as noted on two occasions with this donor. Both of these collections involved apheresis-based collections, with no issues noted for seven other collections from whole blood. Issues with clogged leukoreduction filters have been reported for donors with sickle cell trait and disease (15,16), but similar issues have not been reported with individuals presenting with HbC variants.

The clinical ramifications of transfusing RBCs from donors with hemoglobinopathies are unclear. RBC exchange in HbSS patients aims to reduce the fraction of hemoglobin S cells. While the current best practice is to use HbS-negative RBCs for such procedures, guidelines do not address the use of blood from donors with other hemoglobinopathies. A systematic review reported that transient hemoglobin variants are commonly observed in transfused patients with HbSS, with no reported clinically significant adverse effects (17). Regardless, transfusing HbCC RBC units to patients with hemoglobinopathies is not optimal as it causes increased RBC destruction, increasing the need for RBC transfusions, and possibly increasing the rate of alloimmunization.

Previous literature on this subject has not explicitly described the zygosity status of units used in cases of acquired hemoglobinopathies (Table 3). Post-transfusion hemoglobinopathy testing in these studies primarily examined the recipient’s blood rather than the donor’s. This case involving a donor presumed homozygous for HbCC underscores the complexity of this topic, and the true prevalence of blood donors who are homozygous for hemoglobinopathies remains unknown. Transfusion-acquired hemoglobin variants often present as low, transient peaks on hemoglobin electrophoresis that can create diagnostic confusion if donor history is not available. While no clinical complications were identified in the recipient, further investigation into the prevalence and clinical significance of transfusions involving homozygous hemoglobin variants, or variants with coexisting thalassemias is warranted.

Conclusions

While many reports exist for transfusion-acquired hemoglobinopathies originating from heterozygous donors, this case demonstrates the possibility that homozygous HbCC donors may contribute to acquired variants in transfused patients. This case underscores that, under current FDA regulations, asymptomatic individuals with homozygous hemoglobinopathies may meet donation criteria and enter the blood supply undetected. Although the recipient remained clinically stable, the case highlights important diagnostic and transfusion safety implications, particularly regarding transient hemoglobin variants that may appear after transfusion. These findings suggest potential value in implementing targeted hemoglobinopathy screening in select donor groups such as those with repeated collection issues, or in regions with a higher prevalence of hemoglobin variants. Increased clinician awareness of such transient post-transfusion findings is also essential to prevent diagnostic confusion and to guide the selection of optimal blood products for patients with hemoglobinopathies.

Acknowledgments

We thank Dr. Andre Obua for his assistance in preparing the manuscript.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-2026-1-0004/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-2026-1-0004/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-2026-1-0004/coif). Y.W. serves as an unpaid editorial board member of Annals of Blood from March 2026 to June 2028. The other authors have no 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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Publication of this case report and accompanying images was waived from patient consent according to the University of Miami Institutional Review Board (approval No. 20201331).

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/.

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