Autoimmune Hemolytic Anemia after Non-Myeloablative Stem Cell Transplantation: Association with Rh Alloreactivity Induced by Platelet Transfusions.

There is increasing recognition that autoimmune hemolytic anemia (AIHA) may be associated with alloreactivity to red blood cell antigens (Young et al, Transfusion44: 67, 2004; Zumberg et al, Arch Intern Med16: 285, 2001). We report a patient who developed refractory AIHA and alloantibodies to Rh antigens 3 months after a non-myeloablative haploidentical transplant and our attempt to support her with polymerized human hemoglobin transfusions. This 44 year old AB Rh-negative female with del(7) acute leukemia attained a complete remission after standard antileukemic therapy. One month later, she received a haploidentical stem cell transplant from her A Rh-negative sister; preparative drugs included cyclophosphamide, fludarabine, and alemtuzumab. The transplant failed to engraft, confirmed by chimerism studies, and cyclosporine and mycophenolate prophylaxis was discontinued. Treatment for cytomegalovirus (CMV) antigenemia and staphylococcal bacteremia during the next 6 weeks resulted in severe thrombocytopenia for which she received platelet transfusions. Bone marrow biopsy revealed normal chromosomes and no evidence of leukemia, and her infections resolved. Three months after transplant, she developed Evans’ syndrome with severe AIHA and worsening thrombocytopenia. She had a panagglutinin (DAT IgG+, C3+) and was found to have anti-C, D, and E alloantibodies. Previous indirect antibody screens were negative. For 3 weeks, hemolysis continued unabated, requiring 54 units of blood despite treatment with steroids, rituximab, alemtuzumab, plasmapheresis, and erythropoietin. She developed marked hyperbilirubinemia and acute renal failure and required mechanical ventilation and hemodialysis. CMV assays were negative. Due to concerns that transfusions were playing a role in her multiorgan failure, we requested and received permission, despite doubts of its benefit in this setting, for emergency use of the investigational polymerized pyridoxilated stroma-free hemoglobin PolyHeme TM (Northfield Laboratories Inc). She received 11 units over 56 hours raising her hemoglobin to 7.0 g/dl while her hematocrit dropped to TM was discontinued and red cell transfusions were resumed. She died 2 days later with arrhythmias and shock, despite improvement in the response to blood transfusions. We believe that the allosensensitization to C, D, and E resulted from platelets she received from Rh+ donors after the transplant. We hypothesize that the autoantibodies developed from “epitope spreading” due to the Rh allosensitization (Garratty, Transfusion44:5, 2004) as a consequence of unchecked B cell recovery in the face of T cell immunosuppression related to the immunomodulatory effects of the non-myeloablative transplant. Currently, it is generally advised to give prophylaxis with anti-Rh(D) immunoglobulin only to Rh-negative women of child-bearing age who receive platelets from Rh+ donors. Our experience suggests that every effort should be made to avoid allosensitization in all markedly immunosuppressed patients, particularly during the first year post-transplant, and that anti-Rh(D) immunoglobulin should be administered if platelets from Rh-negative donors are unavailable. These recommendations may be especially important in patients receiving alemtuzumab or other immunomodulatory T cell depletion strategies.