Cold agglutinin disease (CAD) is a clonal B-cell lymphoproliferative disorder and a rare subgroup of autoimmune hemolytic anemia (AIHA). CAD accounts for 15–25% of AIHA and affects mainly middle aged or older individuals. The disease is characterized by the production of autoantibodies by bone marrow-derived clonal B cells which attach to erythrocytes when exposed to cold temperatures (3–4°C), causing agglutination and eventual immune-mediated hemolysis. Erythrocyte hemolysis is dependent on complement activation, which is mediated by the classical pathway. After binding of immunoglobulin M (IgM) to erythrocyte carbohydrate antigens (predominantly I antigen, but occasionally Pr antigen), C1 esterase activates C2 and C4 to generate C3 convertase. C3 convertase cleaves C3 to C3a and C3b, and C3b-opsonized cells are then destroyed by phagocytosis, primarily in the liver. Extravascular phagocytosis is believed to be the primary mechanism of erythrocyte destruction, although in a minority of patients, intravascular hemolysis by the complement membrane attack complex is thought to play a role. 

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