Cold agglutinin syndrome as a secondary disease
usually is associated with a hematologic malignancy (e.g., Waldenström
macroglobulinemia [production of monoclonal IgM paraprotein], multiple
myeloma, lymphomas, Kaposi sarcoma) and infections. Activated B lymphocytes
produce pathogenic antibodies (most commonly monoclonal IgM, rarely IgA or
IgG, directed against the I antigen of the erythrocyte membrane in adults;
rarely the antibodies are targeted against the fetal i antigen). When the
blood cools below the “thermal threshold” (approximately 32°C, i.e.,
in acral areas), these autoantibodies cause red cell agglutination,
slugging, and complement binding in peripheral vessels. Upon returning to
the central circulation (warmer areas), the IgM antibodies dissociate,
leaving complement on the cell surface. In severe cases, the red
cell-antibody complexes activate the complement system, which may result in
intravascular hemolysis. Sequestration of opsonized red cells occurs, mainly
by the Kupffer cells in the liver.