Cold Agglutinin Disease – Diagnostic and Therapeutic Challenges in the Clinical Setting

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA), in which IgM specific antibodies cause the agglutination of red blood cells (RBCs) at temperatures < 37°C and activate the classical pathway of complement leading to extravascular hemolysis, C3b-coated RBCs are phagocytosed by the macrophages of the reticuloendothelial system (predominantly in the liver). Up to date there are two clinical-pathologic entities recognized as distinct with different therapeutic implications: cold agglutinin disease and cold agglutinin syndrome (CAS). Primary CAD is recognised as clonal B-cell lymphoproliferative disorder of the bone marrow, clinical and imagistic evidence of associated malignancy. CAS arises in the setting of an underlying disorder such as infection, autoimmune disease or malignancy (non Hodgkin lymphoma or other malignant process). The diagnosis of CAD is often delayed due to the unpredictable clinical course. In spite of the current therapeutic options which are directed at the pathogenic B cells or the complement system, the low response rates and frequent relapses lead to challenges regarding the management of this disease.