In contrast, AIHA induced by cold agglutinins is complement mediated. These autoantibodies are of the IgM class and cannot interact with Fc receptors because there are no Fc resceptors capable of binding the μ heavy chain. Idiopathic cold agglutinin disease generally is associated with an IgM paraprotein against the "I" antigen, an erythrocyte surface protein. Unlike IgG, which must be cross-linked, pentavalent IgM fixes complement efficiently without cross-linking. After binding to the erythrocyte's surface at low temperature, IgM cold agglutinins activate C1, C4, C2, and C3b. With rewarming, the antibody can dissociate, but C3b remains fixed irreversibly, which can lead to recruitment of the terminal complement components (C5-C9, membrane attack complex) and intravascular hemolysis or C3b receptor-mediated phagocytosis by reticuloendothelial cells.
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