UNEXPLAINED HEMOLYSIS IN A PATIENT WITH SICKLE CELL DISEASE: DAT’S CONFUSING.

Case Presentation: A 17yo female with sickle cell disease (SCD; HbSS genotype) presented with pain crisis and acute chest syndrome. She was treated with appropriate antibiotics (ceftriaxone/cefdinir and azithromycin). During the first few days of her hospitalization, she required 2 pRBC transfusions for down trending hemoglobin (Hb) and low reticulocyte count. On hospital day 11, Hb decreased again and labs were concerning for hemolysis with LDH 4,105 U/L, haptoglobin <20 mg/dL, total bilirubin 7.1 mg/dL (direct 1.6 mg/dL). There was initial concern for delayed hemolytic transfusion reaction (DHTR), though direct antiglobulin test (DAT) was negative. Splenic ultrasound revealed a small, echogenic spleen consistent with autoinfarction. As the Hb continued to downtrend, with nadir of 5.4 g/dl, the patient was started on prednisone, with improvement in her anemia. Drug dependent antibodies to ceftriaxone and cefdinir were negative. Transfusion medicine was consulted and found no supporting evidence of DHTR. DAT-negative hemolytic anemia evaluation sent to a referral lab ultimately returned positive for low affinity IgG autoantibody reactive by 4C LISS Wash IAT, consistent with warm autoantibody hemolytic anemia. The lab confirmed that these antibodies were not from previously transfused blood, supporting that her anemia was due to an autoantibody rather than DHTR. The patient was treated with IVIg, rituximab, and a prolonged steroid taper. After treatment, repeat testing was negative for the previously detected antibody.

Discussion: We present a case of warm autoantibody autoimmune hemolytic anemia (w-AIHA) in a patient with SCD. The diagnosis was delayed due to multiple factors – first, the co-occurrence of SCD clouded the picture, as HbSS itself leads to chronic hemolysis and other crises that can present similarly to AIHA, including splenic sequestration and hyperhemolytic crisis. Furthermore, initial DAT were negative, which is inconsistent with an autoantibody-mediated process.Warm AIHA is the most common type of hemolytic anemia in the general population. If an underlying etiology is not identified, it is considered primary w-AIHA. DAT-negative autoimmune hemolytic anemia is defined by evidence of hemolysis with negative Coombs test. These are identified by more sensitive DAT testing.It is important to note that negative DAT on routine testing does not correlate with the severity of w-AIHA. In fact, DAT-negative AIHA has been associated with higher mortality, possibly related to delayed detection and treatment. In our case, the patient was quickly started on steroids due to high suspicion for DHTR. The treatment for DHTR and AIHA is similar, accounting for her clinical improvement prior to confirmatory test results.

Conclusions: When a patient with SCD presents with hemolysis out of proportion to their baseline, it is important to maintain a broad differential and avoid premature closure, especially when the course is atypical for the initial diagnosis. Despite the more common causes of hemolysis in a patient with HbSS, these patients are also at risk for conditions that affect the general population. If there is concern for antibody-mediated hemolysis (worsening anemia with evidence of intravascular hemolysis) even in the context of negative Coombs, early treatment is recommended while awaiting DAT-negative hemolysis testing due to the high risk for morbidity and mortality.