Abstract Introduction: Hyperhemolysis Syndrome (HHS) is a rare but severe complication of red blood cell transfusion, characterized by the destruction of both the patient's and donor's red blood cells. This condition results in post-transfusion hemoglobin levels lower than pre-transfusion levels, often leading to profound anemia, tissue ischemia, and multiorgan failure. HHS predominantly affects individuals with hemoglobinopathies, particularly sickle cell disease. While the pathophysiology remains poorly understood, proposed mechanisms include bystander hemolysis via complement activation, suppression of erythropoiesis, and macrophage-mediated RBC destruction. Refractory cases of HHS are managed with Eculizumab and Tocilizumab, targeting the complement pathway and macrophage activation, respectively. This review aims to examine the role of Eculizumab and Tocilizumab in the management of Hyperhemolysis Syndrome (HHS) through a comprehensive literature review. Methodology: This review analyzed 22 reported cases of HHS identified through PubMed, Embase, and Google Scholar databases. Results: Please refer to the attached image for the detailed results. The average age of the patients was 29.5 years, with 36.4% male and 63.6% female. All patients, except for Case 12, had underlying hemoglobinopathies. In case 12, HHS occurred in the context of HIV and hepatitis C infection. As previously described in the literature, the most common underlying hemoglobinopathy was sickle cell disease compromising 81.8% of the cases in this review, including two patients with concurrent thalassemia. Most patients were admitted to the hospital and received transfusion either for worsening anemia or vaso-occlusive crisis (81.8%), The average number of transfusion units was 3.4 units, with multiple patients only receiving one unit. On average, HHS developed 5.9 days post-transfusion, with a range of 1 to 14 days. Reticulocytopenia and elevated hemolysis markers were present in all cases except for Case 17, highlighting the critical role of reticulocyte percentage in differentiating HHS from delayed transfusion reactions. All patients received standard therapy of methylprednisolone and IVIG for a range of 1 to 5 days, except for case number 11 that received rituximab and eculizumab without steroids or IVIG. Among the 22 patients, 11 patients received Eculizumab, 10 patients received Tocilizumab and 1 patient received both Eculizumab and Tocilizumab. Dosing duration varied significantly between all cases, emphasizing the need of more studies that look into dosing of these novel therapies in HHS. For example, six patients received only one dose of Eculizumab and one case received one dose Tocilizumab with most of them improving, while other cases received up to 4 doses of either Eculizumab or Tocilizumab, and in case number 7 the patient received 2 doses of Tocilizumab and 2 doses of Eculizumab. Among these patients, six patients also received rituximab either before or after Eculizumab or Tocilizumab, two patients received plasmapheresis, and two patients received hemoglobin-based oxygen carrier-201 (HBOC-201). There were 18 out of the 22 cases that improved, hemolysis subsided and hemoglobin levels improved after treatment, on the other hand, one patient did not improve, and three patients passed away. Conclusion: Emerging evidence from available case reports highlights promising outcomes with the use of tocilizumab and eculizumab in refractory cases of HHS. In addition, these agents offer an opportunity to further understand the underlying pathophysiology of HHS. However, the rarity of the disease poses significant challenges to research. Future studies are essential to deepen our understanding of its pathophysiology and to evaluate the effectiveness and safety profiles of these novel medications.
Aqel et al. (Mon,) studied this question.