Life-Threatening Delayed Hemolytic Transfusion Reaction in a Patient with Sickle Cell Disease: Effective Treatment with Eculizumab Followed By Rituximab
Authors: Weitz Ilene C , Boonyasampant Mark , Kay Brian , Boonchalervichian Chaiyaporn , Liebman Howard A. , Shulman Ira A. 
Published: November 2019

Abstract
Introduction:
We report a life-threatening delayed hemolytic transfusion reaction (DHTR) with hyper-hemolysis syndrome (HHS) in a SCD patient triggered by an anti-IH autoantibody with alloantibody behavior. The intravascular hemolysis was successfully inhibited with Eculizumab therapy. The auto antibody was suppressed with rituximab treatment.
Case Report:
The patient is a 35 year-old African American female with SCD. She was given two red cell units ABO, Rh matched and negative for antigens to her known alloantibodies, before undergoing a laparoscopic cholecystectomy. She discharged with hemoglobin of 8.2 g/dL.
Two weeks later she was admitted with severe fatigue, worsening jaundice, and total body pain. Physical examination was notable for scleral icterus, pale conjunctivae, and a well healed surgical scar on her abdomen. Hemoglobin level was 7.4 g/dL and reticulocyte count was reticulocyte count was 211x103/µl, lactate dehydrogenase (LDH) of 1174 IU/L (nl<225 IU/L ). Vital signs were normal. The next day, she spiked a fever of 39° C and her oxygen saturation dropped to 85-90% on 10 liters oxygen. Hemoglobin precipitously decreased to 3.8 g/dL, LDH greater than 5000 IU/L, total bilirubin 9.8 mg/dL, and haptoglobin less than 20 mg/dL. Serum creatinine (Cr) increased to 2.08 mg/dL from 0.77 mg/dL. Blood and urine cultures were negative. Chest x-raywas negative.
A sample sent to the blood bank demonstrated brown cloudy plasma by visual inspection consistent with intravascular hemolysis. Cross matching of the patient’s plasma with segments from the two previously transfused units now showed incompatibility. The DAT was weakly positive for complement only. Testing performed at the American Red Cross (ARC) Immunohematology Reference Laboratory identified anti-IH cold agglutinin, reactive at room temperature and 37°C. Strong (4+) reactivity was observed with A2, B, and O red cells while weak (1+) reactivity was seen with autologous and A1 red cells. An acid elulate demonstrated strong reactivity with A2 and O red cells and no reactivity with autologous and A1 red cells. Initial 4°C cold agglutinin titer was 512. The high titer anti-IH antibody was of IgM subtype with reactivity with H antigen rich red cells (O and A2).
Despite transfusion of five additional antigen negative RBC units, her hemoglobin further declined to 3.6 g/dL. Reticulocyte count also dropped to 36x103/µl and renal function further deteriorated (Cr = 2.08 mg/dL). Because of the aggressive complement mediated intravascular hemolysis, Eculizumab was given on a compassionate use protocol after approval from the USC Investigational Review Board. Meningococcal vaccination and prophylactic ciprofloxacin were given. Eculizumab dose was 1200 mg weekly for four weeks, followed by 1200 mg every 2 weeks starting on week 5. LDH dropped rapidly > 5000 IU/L to 1626 IU/L by day 12, 747 IU/L at day 22 and 467 IU/L by day 30. By day 7 of Eculizumab treatment, the patient’s hemoglobin stabilized at 5.4 g/dl without further need for transfusion with normalization of the serum creatinine (0.54 mg/dl). Immunosuppressive therapy with rituximab, 375mg/m2 was given weekly for 4 weeks to suppress the IH antibody. The cold agglutinin titer, initially noted to be 1:512, remained at 1:256 at 6 weeks but dropped to 1:4 by week 12.
Discussion:
We report a case of delayed hemolytic transfusion reaction with resultant hyperhemolysis triggered by an anti-IH autoantibody with allo-antibody behavior. The anti-IH was reactive at room temperature as well as 37oC, but only weakly reactive with autologous red cells treated with Rituximab to suppress the cold agglutinin and Eculizumab to block the complement mediated hemolysis
After initiation of Eculizumab therapy our patient’s LDH levels decreased by 40% within the first week, 70% by day 14, and 90% at four weeks with stabilization of her hemoglobin without further transfusion.
Conclusion:
We have described the first reported case of HHS triggered by anti-IH formed as a result of red cell transfusion, successfully treated with Eculizumab and Rituximab.
The rapid hematologic improvement due to Eculizumabv occurred well before the cold agglutinin titer dropped (7 days vs 84 days).
Eculizumab may have utility in the treatment of other cases of severe DHTR, alone or, as in our patient, combined with rituximab.

Disclosures
Off Label Use: Eculizumab for inhibition of complement mediated hemolysis Rituximab for suppression of cold agglutinin. Liebman:Alexion: married to Dr. Ilene Weitz Other.