IgA‐mediated autoimmune hemolytic anemia

An eight-month-old previously healthy girl presented with a one-week history of fever, cough, rhinorrhea, and poor appetite. Initial laboratory findings revealed hemoglobin (Hb) 4.5 g/dL, hematocrit 12%, and mean cell volume (MCV) 121.8 fL with evidence of hemolysis; lactate dehydrogenase was elevated at 497 U/L (<300 U/L), total bilirubin 2.44 mg/dL, haptoglobin <10 mg/dL and absolute reticulocyte count 186 × 109/L (normal 10-100), reticulocyte percentage 23.3%. Peripheral blood film showed spherocytes and erythrocyte agglutination (Figure 1A, Wright-Giemsa stain, original magnification ×50), which falsely elevated the MCV.1-3 Direct antiglobulin test (DAT) was negative for IgG and C3d. The cold agglutinin screen and Donath-Landsteiner test were negative. Hb electrophoresis showed a normal pattern, and the screening test for hereditary spherocytosis was also negative. On ultrasound, her spleen was normal in size for age at 6.3 cm.4 As the blood film strongly suggested an immune mediated hemolytic etiology, further DAT investigation was carried out for IgM and IgA antibodies. It was strongly positive for IgA antiglobulin (Figure 1B), confirming a diagnosis of IgA-mediated autoimmune hemolytic anemia (AIHA). The patient was treated with prednisone to which she responded well, and her Hb improved significantly. The DAT plays a central role in diagnosing AIHA, detecting IgG and C3d on the surface of the red blood cells (RBC). Approximately 3-11% of patients with AIHA are estimated to be DAT-negative.5 There are three main causes of DAT-negative AIHA: (1) RBC-bound IgG immunoglobulin is below the detection limit of conventional DAT reagents, which contain anti-IgG and anti-C3d; (2) RBC-bound IgA or IgM immunoglobulin; and (3) low-affinity IgG autoantibodies.5-7 Although our investigations were sufficient, an eluate using monospecific antisera may detect IgA autoantibodies that are missed by DAT.8 Pure IgA-AIHA is a rare phenomenon and accounts for 0.03% to 4% of DAT-negative AIHA cases.4-7 Reported cases of IgA-AIHA vary in age, etiology, and severity.7, 9-11 Management strategies are similar to other types of AIHA: corticosteroids for the initial therapy with intravenous immunoglobulins, immunosuppressive drugs, rituximab, and splenectomy for refractory cases. In this case, the blood film findings of spherocytes and RBC agglutination were the initial clue to an immune mediated hemolytic mechanism, despite the initial DAT being negative. This case highlights the importance of the blood film interpretation in the investigation of DAT-negative hemolysis. The authors declare no potential conflict of interest. EK, ICY, CCH, and ZS collected and analyzed the data. EK and ZS wrote the manuscript. ICY and CCH reviewed the manuscript. We sincerely thank Jeff Kinney and Laura Aseltine for providing Figure 1B. All authors have reviewed and approved the manuscript.

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