Role of Complement in Autoimmune Hemolytic Anemia

Abstract

The classification of autoimmune hemolytic anemias and the complement system are reviewed. In autoimmune hemolytic anemia of the warm antibody type, complement-mediated cell lysis is clinically relevant in a proportion of the patients but is hardly essential for hemolysis in most patients. Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease, secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria) are entirely complement-mediated disorders. In cold agglutinin disease, efficient therapies have been developed in order to target the pathogenic B-cell clone, but complement modulation remains promising in some clinical situations. No established therapy exists for secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria, and the possibility of therapeutic complement inhibition is interesting. Currently, complement modulation is not clinically documented in any autoimmune hemolytic anemia. The most relevant candidate drugs and possible target levels of action are discussed.

Keywords: Autoimmune hemolytic anemia; Cold agglutinin disease; Complement; Complement inhibitors; Therapy.

Fig. 1

The complement cascade, simplified. Only parts relevant for this review article are shown. Explanation: See text. C = Complement; MAC = membrane attack complex. Originally published in BioMed Res Int 2015 [28]. Copyright: S. Berentsen and T. Sundic. Re-used with permission.

Fig. 2

Erythrocyte destruction in warm-antibody mediated autoimmune hemolytic anemia. Explanation: See text. Ig = Immunoglobulin; C = complement. Originally published in BioMed Res Int 2015 [28]. Copyright: S. Berentsen and T. Sundic. Re-used with permission.

Fig. 3

Complement-mediated hemolysis in cold agglutinin disease (CAD) and cold agglutinin syndrome (CAS). Explanation: See text. CA = Cold agglutinin; C = complement. Originally published in BioMed Res Int 2015 [28]. Copyright: S. Berentsen and T. Sundic. Re-used with permission.

Fig. 4

Biphasic, complement-mediated hemolysis in paroxysmal cold hemoglobinuria (PCH). Explanation: See text. Ig = Immunoglobulin; ag = antigen; ab = antibody; C = complement. Originally published in BioMed Res Int 2015 [28]. Copyright: S. Berentsen and T. Sundic. Re-used with permission.

Fig. 5

Candidate complement modulators and possible levels of therapeutic complement inhibition in autoimmune hemolytic anemias. Explanation: See text. Ig = Immunoglobulin; C = complement, C1-INH = C1 inhibitor. First published in Blood 2014 [11]. Copyright: Blood, the Journal of the American Society of Hematology. Re-used with permission.