Red blood cell transfusion in sickle cell disease: From clinical necessity to immunological complexity

Abstract Sickle cell disease (SCD) is one of the most common inherited haemoglobin disorders worldwide and is associated with substantial morbidity, premature mortality and lifelong healthcare utilisation. Red blood cell (RBC) transfusion remains a cornerstone of SCD management and is indispensable for the treatment and prevention of life‐threatening complications, including acute chest syndrome, ischaemic stroke, severe anaemia and perioperative complications. Despite its undeniable therapeutic benefits, repeated transfusions are accompanied by important adverse consequences, including alloimmunisation, iron overload, delayed haemolytic transfusion reactions and transfusion‐transmitted infections. Beyond haemoglobin S dilution, transfusion therapy interacts with the chronic inflammatory and immune‐activated milieu characteristic of SCD. Persistent haemolysis, endothelial dysfunction, nitric oxide depletion, leukocyte and platelet activation collectively influence both disease severity and transfusion‐related immune responses, thereby contributing to alloantibody formation and other immunological complications. This review provides a comprehensive overview of the clinical indications, transfusion strategies, immunological mechanisms and transfusion‐related complications in patients with SCD. Particular emphasis is placed on the cellular and molecular mechanisms underlying alloimmunisation, including the roles of antigen‐presenting cells, CD4 + T lymphocytes, B cells and regulatory T cells. Contemporary approaches to minimising transfusion‐related complications—including extended antigen matching, molecular RBC genotyping, routine alloantibody screening, iron chelation therapy and emerging immunomodulatory strategies—are critically discussed. In addition, the review highlights regional challenges and evolving transfusion practices in Saudi Arabia, including newborn screening programmes, comprehensive care initiatives, donor–recipient antigen mismatch and implementation of national transfusion strategies. By integrating current evidence from clinical medicine, immunology and transfusion science, this review provides clinicians with an updated framework for optimising transfusion therapy while minimising preventable complications and improving long‐term outcomes in patients with SCD.