Posttransfusion hyperhemolysis is arrested by targeting macrophage activation with novel use of Tocilizumab

Abstract

BACKGROUNDHyperhemolysis syndrome (HHS) is a posttransfusion complication most frequently seen in sickle cell disease (SCD), characterized by rapid destruction of transfused and autologous red blood cells (RBCs), resulting in reticulocytopenia and a decrease in hemoglobin to below pretransfusion levels. Additional RBC transfusion can be life threatening. Most patients improve with intravenous immune globulin and steroids, but in refractory cases, hyperhemolysis may result in multiorgan failure and death in the absence of salvage therapy. The exact pathophysiology of HHS remains uncertain, yet new insights suggest that RBC destruction is driven by activated macrophages. Therefore, we propose that antimacrophage therapy may represent an effective treatment.CASE REPORTA case of life‐threatening HHS, refractory to intravenous immune globulin and steroids, in a patient with SCD is presented. Marked elevation in ferritin, an indirect marker of macrophage activation, a negative direct antiglobulin test, and the absence of RBC alloantibodies was noted. A hemoglobin nadir of 2.1 g/dL and resultant hypoxemia‐induced organ failure prompted the use of tocilizumab, an interleukin‐6 receptor monoclonal antibody. Hemoglobin‐based oxygen carrier‐201, a cell‐free polymerized bovine hemoglobin, was used to support the patient during critical anemia.RESULTSHemolysis resolved and ferritin dramatically decreased after administration of tocilizumab, which was well tolerated. A full recovery was achieved.CONCLUSIONThis case highlights both a novel and successful approach to managing refractory transfusion‐induced hyperhemolysis with tocilizumab and provides further evidence supporting the role for macrophage activation in the destruction of RBCs in antibody‐negative HHS. We propose that tocilizumab is an effective and rapid salvage therapy for refractory HHS.

Hyperhaemolytic Syndrome in Sickle Cell Disease: Clearing the Cobwebs

“…Binding of the antibody to IL-6 receptor inhibits the pro-inflammatory effects of IL-6. An improvement in inflammatory markers has been reported, which further supports the role of macrophage activation in red cell destruction in HS [51,55].…”

Peripartum hyperhemolysis prophylaxis and management in sickle cell disease: A case report and narrative review

“…In this case, with the patient's severely low preoperative Hb, RBC transfusion was necessary before cesarean section. Immunosuppressive agents that have been used successfully for HS treatment include corticosteroids, IVIG, rituximab, eculizumab, bortezomib, and tocilizumab 2,4,33,34 . In many published cases of HS, multiple agents were used in combination.…”

“…Immunosuppressive agents that have been used successfully for HS treatment include corticosteroids, IVIG, rituximab, eculizumab, bortezomib, and tocilizumab. 2,4,33,34 In many published cases of HS, multiple agents were used in combination. Data on the use of immunosuppressants for the prevention of DHTR/HS in SCD are sparse, but rituximab and bortezomib have been used successfully in case reports/series outside of pregnancy.…”

Red cell transfusion and alloimmunization in sickle cell disease

“…[85][86][87][88][89][90][91][92] Case reports have also described treatment of hyperhemolysis with tocilizumab, a monoclonal antibody against the interleukin-6 receptor. [93][94][95] These cases showed marked improvement after targeted antiinterleukin-6 receptor therapy, suggesting that blockade of macrophage activation may be an effective treatment strategy. Table 2 summarizes published reports describing use of eculizumab and tocilizumab in patients with SCD.…”