Cooling of the blood during passage through peripheral vessels allows immunoglobulin M (IgM) cold agglutinin to bind to erythrocytes, causing agglutination and complement protein 1 (C1) fixation. C1 esterase activates C4 and C2, generating C3 convertase, which binds and splits C3, leading to deposition of C3b on the cell surface. During return to the central circulation and subsequent warming, IgM removes into serum and the agglutinated cells are detached from each other. C3b remains bound and could activate C5, leading to the formation of the membrane attack complex and intravascular hemolysis, which seems to play a role during acute exacerbations. In steady state, however, phagocytosis of C3b-coated erythrocytes by reticulo-endothelial cells in the liver is the predominant pathway, resulting in extravascular hemolysis. Intrahepatic C3b conversion leads to deposition of C3d on the surviving erythrocytes, which are released into circulation.8 (Image from Clinical Lymphoma & Myeloma, reprinted with permission.)
