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

<p>Cold agglutinin disease: current challenges and future prospects</p>

“…CA binds to its antigen at the erythrocyte surface during passage through the cooler parts of the peripheral circulation, causing agglutination of red blood cells and complement activation by the classical pathway. 12,16,17,45,46 IgM is a potent classical pathway trigger, and the antigen-IgM complex binds complement protein C1q. C1 esterase then activates C2 and C4, generating C3 con-vertase which cleaves C3 into C3a and C3b.…”

“…In most patients with CAD, the C3b-mediated phagocytosis is considered the predominant hemolytic mechanism during steady-state disease. 16,18,48 The absence, or at least modest role, of terminal pathway activation in stable patients can probably be attributed to the protective effect of CD55 and CD59, which, unlike in paroxysmal nocturnal hemoglobinuria (PNH), are intact in CAD. 16,20 At least in some patients and situations, however, C3 is supposed to initiate the terminal complement cascade by binding and splitting C5, resulting in the formation of the C5b-9 complex (membrane attack complex) and intravascular hemolysis.…”

“…16,18,48 The absence, or at least modest role, of terminal pathway activation in stable patients can probably be attributed to the protective effect of CD55 and CD59, which, unlike in paroxysmal nocturnal hemoglobinuria (PNH), are intact in CAD. 16,20 At least in some patients and situations, however, C3 is supposed to initiate the terminal complement cascade by binding and splitting C5, resulting in the formation of the C5b-9 complex (membrane attack complex) and intravascular hemolysis. 20,49 The occurrence of hemoglobinuria in about 15% of the patients 4 and the rather frequent finding of hemosiderinuria 29 support this notion, as does the beneficial effect of C5 inhibition with eculizumab.…”

“…Complement modulation for treatment of CAD was first described in 2009 and is undergoing rapid development (Figure 2). 16,49,74 The anti-C5 monoclonal antibody, eculizumab, has proved able to inhibit intravascular hemolysis and reduce lactate dehydrogenase levels and transfusion requirements in a prospective study of 13, mostly transfusiondependent patients with CA-mediated hemolytic anemia (12 CAD and one severe CAS). 20 Only a marginal increase in Hb level was observed.…”

“…3,[12][13][14][15] Complement activation via the classical pathway is essential for subsequent hemolysis. [16][17][18][19][20][21] Recent advances in CAD include the demonstration of a distinct clonal B-cell LPD, the documentation of effective B-cell-directed therapies, and the development of novel complement-directed therapies. This review will focus on these achievements, which also raise some challenges.…”