Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA) that accounts for approximately 15%-25% of AIHA cases and is characterized by two interdependent features: a clonal bone marrow B-cell lymphoproliferative disorder producing monoclonal immunoglobulin M (IgM)-κ autoantibodies, and complement-mediated hemolysis driven by the classical pathway. Cold agglutinins bind to erythrocytes at low temperatures and trigger C1-initiated complement activation, predominantly leading to C3b-mediated extravascular hemolysis in the liver, with intravascular hemolysis occurring chiefly during acute exacerbations. CAD must be distinguished from cold agglutinin syndrome (CAS), which occurs secondary to infection, malignant lymphoma, or other disorders, and is managed by treating the underlying cause. The 2022 World Health Organization classification recognized CAD-associated lymphoproliferative diseases as distinct entities. Beyond anemia, patients experience disabling cold-induced circulatory symptoms, profound fatigue, and elevated thromboembolic risk. Diagnosis rests on evidence of hemolysis, a monospecific direct antiglobulin test result positive for C3d but negative for immunoglobulin G (IgG), a cold agglutinin titer ≥ 1:64, and bone marrow evaluation; thermal amplitude can predict clinical severity better than titer alone. Corticosteroids and splenectomy are generally ineffective and not recommended. Contemporary management combines B-cell-directed therapy with complement inhibition, the latter being transformed by the anti-C1s antibody, sutimlimab. This review summarizes the pathophysiology, diagnostic approaches, and rapidly evolving treatment landscapes for CAD, including emerging complement- and clone-directed agents.