Complement-mediated hemolysis in cold agglutinin disease. Antigen-bound CA on the cell surface binds C1q and initiates the classical complement pathway. C1 esterase activates C2 and C4, generating C3 convertase, which results in the cleavage of C3 to C3a and C3b. Upon warming to 37°C, CA detaches from the cell, allowing agglutinated erythrocytes to separate, whereas C3b remains bound. A proportion of the C3b-coated cells is sequestered by macrophages of the reticuloendothelial system, mainly in the liver. On the surface of the surviving RBCs, C3b is cleaved, leaving high numbers of C3d molecules on the cell surface. In some situations, complement activation may proceed beyond the C3b step with cleavage of C5, resulting in activation of the terminal pathway and intravascular hemolysis. C, complement protein. Reprinted from Berentsen and Sundic24 with permission.
