Etiology and treatment of primary cold agglutinin disease. Clonal B cells in the bone marrow produce IgMκ antibodies against the I antigen, which bind to erythrocytes (RBC) at low temperatures. This results in coating of erythrocytes with complement C3b and subsequent destruction by intravascular, but predominantly extravascular, hemolysis in the liver. Treatment strategies include (1) direct targeting of the B-cell clone by rituximab or rituximab-containing immunochemotherapy and possibly B-cell receptor (BCR) or BCL2 inhibitors, or (2) interference with complement coating or erythrocyte destruction.