Case Report: Sickle cell anemia with complex alloimmunization

Introduction

Sickle cell anemia (SCA) is an autosomal recessive genetic disorder characterized by a single mutation in the β-globin gene, which results in the formation of abnormal hemoglobin S (HbS) rather than normal hemoglobin A (HbA) (1). Deoxygenated HbS polymerizes into long chains that distort erythrocyte morphology into a sickle shape, causing severely painful vaso-occlusive crises that can result in stroke, avascular necrosis, nephropathy, retinopathy, and venous thromboembolism (1). SCA patients often present with acute anemia requiring blood transfusion; however, around 15-50% of SCA patients develop complex alloimmunization that can cause delayed hemolytic transfusion reactions (DHTR) (2). Complex alloimmunization can delay safe transfusions due to increased difficulty in finding compatible blood and may preclude SCA patients from curative therapies (2). While complex alloimmunization usually presents with alloantibodies against Rhesus (Rh) and Kell antigens, rarer alloantibodies may also develop with repeated transfusions (2). We present a 45-year-old male SCA patient with rare complex alloimmunization which requires systemic immunosuppression and complicates future blood transfusions.

Case

A 45-year-old male with a history of sickle cell anemia presented to the emergency department with progressively worsening pain in the ankles, back, and shoulders for five days. He described the pain as 10/10 in severity and consistent with prior episodes of sickle cell pain crisis. His symptoms were uncontrolled with his home regimen of hydrocodone-acetaminophen (5–325 mg every four hours as needed). The patient denied shortness of breath, chest pain, recent travel, or trauma.

Two months prior, the patient had been hospitalized for an acute sickle cell crisis, during which he received three crossmatched units of packed red blood cells for treatment of symptomatic anemia (Hgb 7.1 g/dL). Following transfusion, he developed a febrile non-hemolytic transfusion reaction characterized by a two-degree temperature increase and tachypnea, requiring rapid response management. At that time, no overt evidence of hemolysis was identified. However, over the next few days, he experienced a progressive decline in hemoglobin to 4.7 g/dL, falling below his pre-transfusion baseline and raising concern for hyperhemolysis syndrome versus warm autoimmune hemolytic anemia. Laboratory evaluation demonstrated worsening hemolysis, with lactate dehydrogenase increasing from 529 U/L pre-transfusion to 1895 U/L post-transfusion and persistent hyperbilirubinemia (total bilirubin 6.2 mg/dL pre-transfusion to 5.4 mg/dL post-transfusion). Hemoglobin electrophoresis showed a decline in donor hemoglobin A from 34% to 19% and an increase in hemoglobin S from 59% to 73%, suggesting destruction of both transfused and native red blood cells. Reticulocyte counts remained elevated (10.2% pre-transfusion and 9.4% post-transfusion). Subsequent hematologic evaluation revealed a newly positive antibody screen, and retrospective crossmatching showed that at least one previously transfused unit was incompatible. Direct antiglobulin testing became positive following transfusion (IgG 3+). Elution studies were attempted but were invalid due to reactivity with the internal control, and alloadsorption studies were also inconclusive. The patient had previously undergone red blood cell genotyping demonstrating anti-D, anti-E, anti-C, and anti-Kell antibodies. Additional studies performed at an outside reference laboratory demonstrated broad reactivity without identification of a specific antibody. Further evaluation at the reference laboratory subsequently identified a new anti-Fy3 alloantibody. Extended red blood cell genotyping revealed the patient was homozygous for the FY*02N.01 (c.-67T>C) GATA-associated Duffy-null promoter variant, resulting in a predicted Fy(a-b-) erythrocyte phenotype. The patient’s sample demonstrated additional unresolved reactivity so compatible blood products were limited to units negative for D, C, E, K, Fya, Fyb, Jkb, and s antigens. Hematologic evaluation ultimately identified anti-Fy3, anti-Jsa, and anti-Doa, making compatible blood products unavailable. Hematology recommended that future transfusions be reserved for life-threatening emergencies and require both cytopathologist and blood bank approval. The patient was treated with methylprednisolone, intravenous immunoglobulin (IVIG), erythropoietin, and folic acid.

On presentation to the emergency department, the patient was afebrile, mildly tachycardic (101 bpm), and had an oxygen saturation of 92% on room air. His physical exam was otherwise unremarkable. Laboratory evaluation revealed severe normocytic anemia with hemoglobin of 5.4 g/dL and an appropriate reticulocytosis (17.0%). Peripheral smear demonstrated significant red blood cell sickling. A CMP showed normal electrolyte levels and kidney function, with mild elevations in AST (76 U/L) and total bilirubin (2.9 mg/dL), findings consistent with hemolysis.

The patient was diagnosed with vaso-occlusive sickle cell pain crisis. Hematology was consulted due to his known alloimmunization significantly limiting the availability of compatible blood products. He was managed with hydromorphone patient-controlled analgesia (PCA) for pain control, continuous intravenous 0.9% sodium chloride (75 mL/hr), intravenous immunoglobulin (single dose 400 mg/kg), intravenous methylprednisolone (40 mg every 12 hours) transitioned to an oral prednisone taper, and epoetin alfa-epbx (10,000 units subcutaneous injection for two doses). He also received folic acid-vitamin B6-vitamin B12 (2.5-25–2 mg PO daily) and vitamin C (500 mg PO three times daily) supplementation per Hematology recommendations. Hydroxyurea therapy was not pursued due to a history of myelosuppression. Given the limited treatment options in the setting of severe alloimmunization and chronic hemolytic anemia, initiation of mitapivat, a pyruvate kinase activator shown to reduce hemolysis by increasing ATP in red blood cells, was considered (3). Transfer to a tertiary care center for further management and possible initiation of mitapivat was attempted, but was not possible due to limited bed availability.

During hospitalization, the patient’s hemoglobin stabilized between 6.0-6.5 g/dL and his pain gradually improved. On hospital day eight, he was transitioned from PCA to oral oxycodone/acetaminophen with IV hydromorphone as needed for breakthrough pain. Although he remained fatigued due to his persistent anemia, the patient was clinically stable and felt prepared to manage his symptoms at home. The patient was discharged home with a pain management regimen and a plan for close outpatient follow-up, including weekly hemoglobin checks. The clinical course across both hospitalizations is summarized in Figure 1.

Discussion

Red Blood Cell (RBC) transfusion remains a critical component of care in SCA for acute and chronic complications, including severe symptomatic anemia, acute chest syndrome, and stroke (4). However, repeated transfusion exposure can lead to alloimmunization and delayed hemolytic transfusion reactions, particularly in heavily transfused patients. Alloimmunization is especially relevant in SCA, where alloantibody formation occurs more frequently than in the general transfused population and can substantially complicate future care (4). The reasons for the increased alloantibody formation rate in this population are poorly understood, but risk factors such as Rh genetic diversity between recipients and donors, large transfusion burdens, and inflammatory components of SCA have been identified (4).

Current literature shows that alloimmunization most commonly involves antibodies to the Rh and Kell blood group systems, particularly anti-C, anti-E, and anti-K (4). This case is notable for the development of anti-Fy3, anti-Jsa, and anti-Doa, each of which presents distinct challenges for transfusion management. Anti-Fy3 is directed against a high-prevalence Duffy antigen. The patient’s homozygous FY02N.01 (c.-67T>C) GATA-associated Duffy-null genotype predicts an Fy(a-b-) erythrocyte phenotype because the promoter variant disrupts GATA-1-mediated erythroid expression of ACKR1/Duffy (5). This distinction is clinically important because the GATA-associated Duffy-null phenotype is erythroid-restricted rather than a complete absence of Duffy expression; DARC/ACKR1 expression is preserved in non-erythroid tissues, including endothelial cells (5, 6). Consequently, individuals with this genotype are generally not expected to form anti-Fyb despite serologically typing Fy(b-), because Fyb is expressed outside erythrocytes (7). The development of anti-Fy3 in this setting is therefore a different and clinically significant phenomenon. Fy3 is a common epitope on the FY protein separate from the Fya/Fyb polymorphism, and patients with the GATA promoter mutation remain at risk for clinically significant anti-Fy3 (7). This is unusual despite the high prevalence of the Duffy-null phenotype in populations of African ancestry: Howes et al. showed that the silent FYBES variant commonly reaches fixation across stretches of sub-Saharan Africa, while Stone et al. noted only five prior case reports of acute or delayed hemolytic transfusion reactions due to anti-Fy3 (7, 8). More recently, Lemaire and Waldvogel Abramowski described three additional patients with SCD who developed anti-Fy3 alloimmunization despite being homozygous for FY*02N.01; two were described as being in a transfusion deadlock (9).

Compatible blood is difficult because anti-Fy3 requires Fy(a-b-) units; Fy(a-b-) units are primarily found in donors of African ancestry, and matching may be difficult when multiple alloantibodies coexist (7). Donor demographics therefore matter: Hirani et al. reported Fy(a-b-) in 0.2% of donors with Fy antigen testing; in their regional analysis, Fy(a-b-) represented 2.6% of tested donors born in Africa (10). In this patient, concomitant anti-Jsa and anti-Doa further narrowed the compatibility search, and anti-Doa has been associated with recurrent hemolytic transfusion reactions not detected by crossmatching (11). Thus, this case combines a rare Duffy-related donor-supply problem with additional antibody-driven compatibility limitations, making the patient’s anti-Fy3 alloimmunization a central educational feature of the case.

The combination of a recent febrile non-hemolytic reaction, subsequent hemolytic concern, and rare alloantibodies in our patient meant that transfusion could no longer be approached as routine supportive therapy despite severe anemia. The ASH 2020 guidelines suggest immunosuppressive therapy (IVIG, corticosteroids, and/or rituximab) for SCA patients who have an acute need for transfusion but for whom compatible blood cannot be identified (4). Our patient’s management was guided by this specific indication, as compatible blood was unavailable due to his rare antibody combination. Importantly, the patient’s initial febrile non-hemolytic transfusion reaction was immunologically distinct from the subsequent hemolytic concern; the later hemoglobin decline, DAT positivity, incompatible retrospective crossmatch, and antibody workup were the features that raised concern for hyperhemolysis/warm autoimmune hemolytic anemia and for future hemolytic reactions with incompatible units. Epoetin alfa was initiated to stimulate endogenous erythropoiesis given the inability to correct his anemia through transfusion (4).

In this case, the combination of IVIG, corticosteroids, and epoetin alfa allowed hemoglobin stabilization without transfusion, consistent with the guideline recommendation to avoid further transfusion except in life-threatening anemia with ongoing hemolysis (4).

The most likely mechanism of IVIG stabilizing the patient is by decreasing immune-mediated destruction of red blood cells (12). It may do this by blocking Fcγ receptors on macrophages, which reduces removal of antibody-coated red blood cells (12). IVIG may also increase clearance of circulating alloantibodies through FcRn saturation and may neutralize alloantibodies through anti-idiotypic interactions (13). Corticosteroids likely contributed by inhibiting Fc receptor-mediated clearance of sensitized red blood cells and, over time, reducing alloantibody production (14). Epoetin alfa supported the patient’s own red blood cell production, reducing reliance on transfusion in a patient for whom additional blood products carried high risk (15). Together, these therapies targeted both ongoing red blood cell destruction and insufficient red blood cell production.

This case report has several limitations. It describes a single patient, therefore the findings cannot be generalized. The relationship between the febrile non-hemolytic transfusion reaction and the identified alloantibodies was not definitively established. The follow-up period was limited, as the patient was discharged with a hemoglobin of 6.0-6.5 g/dL and long-term outcomes are unavailable. Transfer for pyruvate kinase activator therapy was not achieved, limiting assessment of this intervention.

This case underscores the importance of transfusion stewardship and alloimmunization prevention strategies. Current guidelines recommend prophylactic Rh (C, E, c, e) and K antigen matching for all SCA patients, even in the absence of alloantibodies, to reduce the risk of alloimmunization (4). For patients who develop alloantibodies, extended phenotype matching and molecular genotyping of donor units may help prevent further sensitization; however, the limited availability of such units must be balanced against the risk of delaying necessary transfusions. Further research should focus on developing evidence-based management strategies for SCA patients with rare alloantibodies that preclude transfusion.

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Footnotes

Edited by: Samit Ghosh, University of Pittsburgh, United States

Reviewed by: Xiang-An Li, University of Kentucky, United States

Melca Barros, Federal University of São Paulo, Brazil