Red blood cell‐directed immune responses in COVID ‐19: Mechanisms, clinical evidence and implications for transfusion medicine

SARS-CoV-2 infection is associated with a broad spectrum of red blood cell (RBC)-directed immune responses, ranging from isolated direct antiglobulin test (DAT) positivity to autoimmune hemolytic anemia (AIHA) and transfusion-related diagnostic challenges. This narrative review integrates current evidence on the mechanisms underlying these abnormalities, their clinical manifestations, and their implications for transfusion medicine. Molecular mimicry, bystander B-cell activation, complement dysregulation, oxidative membrane injury, and structural erythrocyte remodeling appear to represent interconnected mechanisms promoting immune recognition and altered function of RBCs. DAT positivity is frequently observed in hospitalized patients with COVID-19, often in the absence of clinically significant hemolysis, emphasizing that a positive DAT should not be considered synonymous with AIHA. Autoantibodies, complement deposition, and occasional alloimmune responses may complicate antibody identification, compatibility testing, and selection of appropriate blood components. Available evidence remains limited by heterogeneous study designs and the predominance of observational studies and case reports. Recognition of RBC-directed immune responses as part of COVID-19-associated immune dysregulation may improve interpretation of immunohematological findings, facilitate appropriate transfusion support, and help distinguish clinically significant immune hemolysis from isolated serological abnormalities.