SummaryMost haemolytic disease is mediated by immunoglobulin G (IgG) antibodies and leads to red blood cell destruction outside of the circulatory system. However, rare syndromes, such as paroxysmal cold haemoglobinuria, show IgG antibodies causing intravascular destruction. Haemolysis may also occur because of immunoglobulin M antibodies. Historically, these antibodies have been termed 'cold agglutinins' because they cause agglutination of red blood cells at 3°C. Cold agglutinin haemolytic anaemia has been associated with a number of autoimmune and lymphoproliferative disorders, and its management differs substantially from warm antibodymediated haemolytic anaemia. This review of cold haemolytic syndromes describes new therapies and clinical strategies to determine a correct diagnosis.Keywords: cold agglutinin, IgM monoclonal protein, MGUS, paroxysmal cold haemoglobinuria, Waldenström macroglobulinaemia.
Paroxysmal cold haemoglobinuriaParoxysmal cold haemoglobinuria was first recognised as a distinct clinical entity in 1872 (Crosby, 1952), and the haemolytic antibody was described by Donath and Landsteiner (1904). Landsteiner later received the 1930 Nobel Prize in Medicine for his discovery of the ABO blood groups (Win et al, 2005). The antibody first was observed as a cross-reacting antibody to an antigen on Treponema pallidum and frequently was detected in patients with secondary or tertiary syphilis. Obviously, this is now rare. Today, it is identified in children with postviral illness, much like immune thrombocytopenic purpura. Albeit severe, paroxysmal cold haemoglobinuria is not persistent and generally is not a chronic disorder.The test for paroxysmal cold haemoglobinuria [detection of the haemolytic (anti-P) antibody] is simple to perform. In its original description, 2 aliquots of the patient's red blood cells are collected. One is incubated for 60 min at 37°C, and the other is incubated for 30 min at 3°C and then 30 min at 37°C. The blood is centrifuged, and the plasma is inspected for evidence of haemoglobin. Although it was not understood at the time the test was developed, complement-mediated haemolysis in the control tube (with never-chilled blood) does not occur because anti-P antibodies do not bind the red blood cell surface and complement is never fixed. In the second tube, incubation at 3°C allows binding of the polyclonal anti-P antibody and complement fixation. Subsequent warming to 37°C allows complement activation (C4 through C9), red blood cell lysis and intravascular haemoglobin release.False-negative findings may occur with the Donath-Landsteiner test. If additional complement is not added to a blood specimen, lysis of cell membranes may not occur. Modern iterations of the Donath-Landsteiner test add complement to the specimens to guard against its depletion (a consequence of prior consumption by the antibody). The anti-P antibody also may be consumed by haemolysis. Further modifications of the assay include incubation of papain-treated group-O cells with the plasma. Papain digests the...