Cold agglutinin disease: pathology, diagnosis, and treatment

Abstract

Cold agglutinin disease (CAD), an immune hemolytic disease mediated by the classical complement-dependent pathway, accounts for approximately 8% of autoimmune hemolytic anemia (AIHA) cases. Primary CAD is a clonal B-cell lymphoproliferative disease of the bone marrow that produces IgM type-M protein, while conventional secondary CAD is cold agglutinin syndrome (CAS). Clinical findings are broadly classified into chronic anemia due to hemolysis and symptoms associated with peripheral circulatory failure due to erythrocyte aggregation under cold exposure. Not all patients require drug therapy, but monoclonal antibody therapy against complement C1s is preferred for the former presentation and B-cell suppressors for the latter. As cold AIHA is treated differently than warm AIHA, misdiagnosis can significantly impact the outcome of treatment. The most important aspect of blood testing is temperature control of specimens. Cold agglutinin titer, IgM quantification, electrophoresis, and immunofixation methods may produce false-negative results if the serum is not temperature-controlled at 37-38°C until serum separation. Correct handling of specimens, along with knowledge of the various clinical features of CAD, will lead to correct diagnosis and appropriate treatment.