Pure IgA-mediated hemolytic anemia. a rare and challenging diagnosis of “Coombs Negative” hemolytic anemia, with successful management Free

Background: The diagnostic approach for patients with hemolytic anemia, typically involves assessment of an immune versus non-immune mechanism, i.e. direct antiglobulin test (DAT) for IgG and/or C3d. Management then is directed to the underlying etiology, whether IgG, IgM/complement, or non-immune mechanism. We present a very rare case where this approach did not apply: pure IgA-mediated hemolytic anemia, with consistently negative DAT for IgG and C3d.

Case Presentation: A 39-year-old woman, with no past history of anemia, developed severe anemia over 3 months. At an outside hospital, her hemoglobin (Hgb) levels had been as low as 5.9 gm/dL, requiring transfusion of approximately 30 units of packed red cells in the prior 3 months. Bone marrow biopsy showed mild dyserythropoiesis, marked erythroid hyperplasia, and normal iron stores. No diagnosis was made, and she received no treatment except transfusions. She was transferred to our hospital for hematology consult.

At our initial visit, laboratory findings were indicative of hemolytic anemia. Absolute reticulocyte count was 0.26 X 10^9/L (Nl: 0.02-0.08), with her reticulocyte percent as high as 46.0% (Nl: 0.5-2.0%). Haptoglobin was <10 mg/dL (Nl: 43-212), LDH 1,186 U/L (Nl: 100-200). Total bilirubin was modestly elevated, 2.1 mg/dL (Nl 0.2-1.2 mg/dL), predominantly unconjugated. DAT was repeatedly negative for IgG and C3d. Fluorescein-labeled proaerolysin (FLAER), Donath-Landsteiner testing, and eosin-5'-maleimide test for were all negative. Hemoglobin electrophoresis was normal. Genetic panel (37 genes) for hereditary hemolytic anemia was unrevealing. Aggressive hemolysis persisted requiring 5 red cell transfusions in 2 weeks.

Notably, multiple specimens sent for peripheral smear review were rejected by the lab due to “Specimen unsuitable for testing due to hemolysis.” Ultimately, peripheral smear was obtained and revealed anisopoikilocytosis, marked polychromasia, and red cell agglutination. The Soluble C5B-9 (SC5B-9) complex level was markedly elevated (>1200 pg/mL, Nl < 250) Based on the

agglutination and SC5B-9 complex level, she received two weekly doses of sutimlimab, without impact on her anemia or hemolysis markers.

In the absence of an identified etiology for the critical hemolytic anemia, we reconsidered the possibility of an immune-mediated process. An extended DAT was obtained (VERSITI reference lab). The results were weakly positive for polyspecific DAT, negative for IgG, C3b, C3d, but strongly positive (4+) for IgA. We therefore arrived at the diagnosis of pure IgA-mediated, immune hemolytic anemia.

The patient received a course of dexamethasone IV 40 mg X 4 days and IVIG 1 gram/Kg, daily X2. Within 2 weeks of the dexamethasone/IVIG, the patient's Hgb increased from 7.8 gm/dL to 12.0 gm/dL, the LDH declined from 1523 to 284 and the SC5B-9 normalized. She was transitioned to prednisone at discharge, and the dose was gradually tapered to 20 mg daily, without relapse 10 months later.

Conclusions: Educational Points: “When you have eliminated all which is impossible, then whatever remains, however improbable, must be the truth,” per Sherlock Holmes, in The Sign of Four, Sir Arthur Conan Doyle. This case illustrates a true diagnostic dilemma, as the standard approach to the diagnosis of severe, life-threatening hemolytic anemia was unrevealing. It was only when we considered an improbable etiology, i.e. pure IgA-mediated immune hemolytic anemia, despite repeated negative DAT, did we identify the diagnosis.

The true incidence of pure IgA-mediated immune hemolytic anemia is unknown, as the diagnosis is not easy to make, but is extremely rare. In one study of 5235 patients with immune hemolytic anemia, over a 14-year period, 124 patients had IgA antibodies to red cells detected. However, only 6 had IgA without concomitant IgG or IgM. (Sokol, RJ. e al. Transfusion 1997). Those 6 patients had C3d present and 3 also had C3c.

Only one other case of Pure IgA-mediated hemolytic anemia, without C3d, has been reported. (Chadebech P et al, Blood 2010). In this case, complement activation was believed to be the mediator of hemolysis. And while sutimlimab did not resolve the hemolysis, glucocorticoids and IVIG rapidly resolved the hemolysis, without relapse.