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Autoimmune hemolytic anemias associated with "Cold" antibodies
Last reviewed: 06.07.2025
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Red blood cell antibodies that become more active at low body temperatures are called "cold" antibodies. These antibodies belong to the IgM class, and complement is required for their activity to manifest. IgM activates complement in the extremities (hands, feet), where the temperature is lower than in other parts of the body; the complement cascade is interrupted when red blood cells move to warmer areas of the body. Natural cold agglutinins in low titers (1:1, 1:8, 1:64) are found in 95% of healthy people. In the presence of an extremely high titer of "cold" antibodies, severe episodes of intravascular hemolysis with hemoglobinemia and hemoglobinuria and occlusion of the microcirculatory bed may develop when the patient is overcooled.
Autoimmune hemolytic anemias with complete cold agglutinins occur in the presence of idiopathic parathyroidism or as a consequence of mycoplasmal infection, Epstein-Barr virus infection, including infectious mononucleosis, cytomegalovirus infection, epidemic mumps or lymphoma. Cold agglutinins are usually polyclonal and directed against erythrocyte antigens I (in infections caused by Mycoplasma pneumoniae) or i (in infections caused by Epstein-Barr virus). Polyclonal cold agglutinins can also be produced in cytomegalovirus infection, listeriosis, epidemic mumps, syphilis, and systemic connective tissue diseases. Monoclonal cold antibodies are produced in Waldenstrom's macroglobulinemia, lymphoma, chronic lymphocytic leukemia, Kaposi's sarcoma, myeloma. Hemolysis is self-limited, treatment is symptomatic.
Paroxysmal cold hemoglobinuria is a rare form of hemolytic anemia, in which "cold" antibodies of a specific type (Donath-Landsteiner hemolysins) with anti-beta specificity are present. The disease can be both idiopathic and caused by viral infections (mumps, measles) or tertiary syphilis. The main thing in treatment is to exclude the possibility of hypothermia.
In older people (50-80 years), chronic cold agglutinin syndrome may be observed, which is often associated with the formation of monoclonal IgM antibodies and lymphoproliferative disorders (chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia). Mild anemia usually occurs, but severe intravascular hemolysis and renal failure sometimes develop. In all cases, hypothermia must be treated; corticosteroids may be prescribed. Splenectomy is not recommended, since red blood cells are eliminated mainly in the liver, not in the spleen.
Diagnostics
The diagnosis of autoimmune hemolytic anemias is confirmed by a positive direct Coombs test (direct antiglobulin test) or sensitized Coombs test (polybrene test). The use of antibodies against IgG, IgM and C3d in the Coombs reaction allows one to determine the isotype of antibodies and complement fixation. In case of a negative Coombs test, detection of antibodies bound to erythrocytes should be taken into account only in the presence of other signs of autoimmune hemolysis. The indirect Coombs test, which reveals anti-erythrocyte antibodies in the blood serum, is not related to the diagnosis of autoimmune hemolytic anemias.