Abstract
Hyperhemolysis syndrome (HHS) is a rare, life-threatening complication of red blood cell (RBC) transfusion characterized by fevers, pain, reticulocytopenia and hemolysis of both native and allogeneic RBCs. Management is not standardized. While the pathophysiology remains uncertain, one of the proposed mechanisms includes macrophage activation, the presence of which is associated with hyperferritinemia. The anti-human interleukin-6 receptor monoclonal antibody, tocilizumab, blunts macrophage activation and may represent a novel treatment option. In cases of critical anemia where further RBC transfusion is contraindicated, support with hemoglobin-based oxygen carriers, such as HBOC-201, a purified polymerized bovine hemoglobin (Hb), may be lifesaving while awaiting native hemoglobin recovery. We report the successful use of tocilizumab supported with HBOC-201 in a sickle cell disease (SCD) patient with life-threatening acute HHS refractory to standard IVIG and steroid therapy who experienced a Hb nadir of 2.1 g/dL.
A 36 year old woman with SCD and extensive RBC alloimmunization presented with symptomatic anemia. Hb was 5.5 g/dL. Plasma ferritin was 157 ng/mL (range 13 - 150 ng/mL). She was transfused phenotypically-matched RBCs. Post-transfusion Hb was 8.8 g/dL. Six days later, she presented with fevers and generalized pain. She was tachycardic and febrile. IV fluids, analgesia, and levofloxacin were initiated. Hb was 6.4 g/dL with evidence of intravascular hemolysis. Direct anti-globulin test (DAT) was negative and no new RBC alloantibodies were identified. Infectious work-up was negative. On hospital day (HD) 2, Hb was 5.1 g/dL. Relative reticulocytopenia was noted. She remained symptomatic; therefore, an additional transfusion was administered with no improvement in post-transfusion Hb. Suspecting acute hyperhemolysis, methylprednisolone and IVIG were initiated. Hb dropped to 3.3 g/dL. Hemodynamic monitoring revealed high-output heart failure. After 3 days of immunosuppression, persistent symptomatic anemia prompted another transfusion. She experienced immediate generalized pain and the transfusion was promptly discontinued. Hb nadir was 2.1 g/dL. Rituximab and eculizumab, the use of which has previously been described with limited success were considered, but were not used given her persistently negative DAT and lack of new RBC alloantibodies. Additional work-up revealed a significant (100-fold) rise in ferritin from 157 ng/mL to 16,300 ng/mL. Due to severe hemolysis and evidence of macrophage activation, novel therapy with tocilizumab was administered. Ferritin immediately down-trended, Hb stabilized, and hemolysis resolved, but organ-threatening anemia prompted use of HBOC-201, obtained through an expanded access IND. Heart rate decreased and oxygenation and mentation improved markedly with HBOC-201. However, after several infusions, she experienced status epilepticus. Brain MRI revealed migroangiopathic thrombotic phenomenon. Blood methemoglobin level was 34.8% (range 0.4 - 1.5). Ascorbic acid was increased and IV methylene blue was administered. Support continued with erythropoietin, cyanocobalamin, and folic acid. By HD 23, native Hb was 8.8 g/dL. She achieved complete recovery.
HHS is most commonly described in SCD and is increasingly recognized. In refractory cases, mortality is high and treatment options are limited. The pathogenesis of HHS is complex and remains unclear. However, it is known that HbS cells adhere to macrophages more readily than HbA cells due to aminophosphatide exposure on the outer membranes of the sickled RBC. At baseline, macrophages appear primed in SCD. Fevers, pain, and marked hyperferritinemia seen in HHS suggest further macrophage activation. Therefore, a treatment strategy targeting this mechanism, such as tocilizumab, is proposed. Efficacy of therapy can be monitored by reduction in ferritin and recovery of red cell indices. HBOC-201 is acellular with no observable immunologic side effects. In patients with extensive RBC alloimmunization for whom compatible blood products are unavailable or not recommended (as in HHS), HBOC-201 may serve as a bridge for increased oxygen delivery until native marrow recovery. This is the first reported case of life-threatening, refractory HHS successfully treated with tocilizumab and supported with HBOC-201. Further study of this treatment approach is warranted.
No relevant conflicts of interest to declare.
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