Complement Activation and Inhibition in Autoimmune Hemolytic Anemia: Focus on Cold Agglutinin Disease

The classical complement pathway and, to some extent, the terminal pathway, are involved in the immune pathogenesis of autoimmune hemolytic anemia (AIHA). In primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria, the hemolytic process is entirely complement dependent. Complement activation also plays an important pathogenetic role in some warm-antibody AIHAs, especially when immunoglobulin M is involved. This review describes the complement-mediated hemolysis in AIHA with a major focus on CAD, in which activation of the classical pathway is essential and particularly relevant for complement-directed therapy. Several complement inhibitors are candidate therapeutic agents in CAD and other AIHAs, and some of these drugs seem very promising. The relevant in vitro findings, early clinical data and future perspectives are reviewed.