Cold agglutinin disease (CAD) is a form of autoimmune hemolytic anemia (AIHA) caused by IgM autoantibodies (cold agglutinins) that bind to red blood cell surface antigens at temperatures below core body temperature (optimally at 0-4C but pathogenic antibodies with high thermal amplitude can bind at temperatures approaching 37C). These IgM cold agglutinins are primarily directed against the I/i antigen system on the RBC surface -- the I antigen is expressed on adult RBCs while the i antigen predominates on fetal and neonatal RBCs. CAD accounts for approximately 15-25% of all AIHA cases and has a median age of onset of 65-70 years. The disease exists in two forms: primary (idiopathic) CAD, which is now recognized as a clonal lymphoproliferative disorder of B lymphocytes (classified by WHO as a distinct entity related to but separate from lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia), and secondary cold agglutinin syndrome, which occurs in association with lymphoproliferative disorders (CLL, lymphoma, Waldenstrom) or infections (Mycoplasma pneumoniae, Epstein-Barr virus/infectious mononucleosis -- typically transient and self-limited). The pathogenesis involves complement-mediated hemolysis rather than the antibody-dependent cellular cytotoxicity that characterizes warm AIHA....