Transfusion of red blood cells (RBCs) can be lifesaving for individuals living with sickle cell disease (SCD). However, alloimmunization following transfusion is more common with SCD than other patient populations, resulting in morbidity and mortality. Management of complications related to RBC alloantibodies, including delayed hemolytic transfusion reactions (DHTRs) and identifying compatible RBCs for future transfusions, remains a challenge for hematologists and transfusion medicine providers. Although transfusion guidelines from organizations including the American Society for Hematology provide general recommendations, individual cases remain challenging. Antibody evanescence and the lack of widespread RBC alloantibody data sharing across hospitals pose unique challenges, as do RH variants in both transfusion recipients and blood donors. Further, as potentially curative therapies require RBC transfusions to lower the hemoglobin S prior to cellular therapy collections and infusions, highly alloimmunized patients may be deemed ineligible. The cases described are representative of clinical dilemmas the authors have encountered and the approaches are as evidence-based as the literature and the authors' experiences allow. A future desired state is one in which RBC alloantibody data are efficiently shared across institutions, Rh alloimmunization can be mitigated, better treatments exist for DHTRs, and a label of "difficult to transfuse" does not prevent desired therapies.
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