Cold Agglutinins

Ten Feizi, Glycosciences Laboratory, Imperial College School of Medicine, Northwick Park Hospital, Harrow, UK

Cold agglutinins are autoantibodies of low affinity which agglutinate erythrocytes at temperatures below 37°C, and optimally at 4°C. Sera of the majority of healthy adults contain harmless cold autoagglutinins at low titers (1 : 2 to 1: 32). Sera of newborns usually do not contain cold agglutinins; they become detectable during the first year of life. The majority of these naturally occurring autoantibodies are directed at the I or i antigens. Raised levels of cold agglutinins occur a) transiently following certain infections, for example with Mycoplasma pneumoniae and Epstein-Barr virus (anti-i), and b) persistently in a chronic relatively benign lympho-proliferative disorder termed chronic cold agglutinin disease. Raised levels of cold agglutinins may go unnoticed, and are frequently detected incidentally during blood cross-matching or other hematological investigations. The antibodies of certain individuals however, cause clinical symptoms: cyanosis (blueness) with impaired circulation at the extremities upon exposure to the cold resulting from erythrocyte autoagglutination, or an autoimmune hemolytic disorder associated with a positive Coombs' (antiglobulin) test resulting from coating of erythrocytes with the complement components C3 and C4. The severity of the symptoms does not necessarily correlate with the cold agglutinin titers measured at 4°C, rather it is thought to be a reflection of the relatively high binding affinities of the antibodies in certain patients.

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