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Cold agglutinin disease

Stanley L Schrier, MD
Section Editor
William C Mentzer, MD
Deputy Editor
Jennifer S Tirnauer, MD


Cold agglutinin disease (ie, cold agglutinin associated autoimmune hemolytic anemia [AIHA]) is typically characterized by the presence of clinical symptoms related to exposure to cold, hemolytic anemia, and antibodies (most commonly IgM, rarely IgA or IgG) directed against polysaccharide antigens on the red blood cell surface that are responsible for the agglutination of red cells at low temperatures [1]. (See "Pathogenesis of autoimmune hemolytic anemia: Cold agglutinin disease".)

This topic will review the clinical manifestations, diagnosis, and treatment of AIHA due to cold agglutinins [2]. Paroxysmal cold hemoglobinuria, another form of cold-related hemolysis, as well as the clinical features and treatment of AIHA due to warm agglutinins, are discussed separately. (See "Paroxysmal cold hemoglobinuria" and "Warm autoimmune hemolytic anemia: Clinical features and diagnosis" and "Warm autoimmune hemolytic anemia: Treatment".)


Cold agglutinin disease is rare, most often affecting females in the seventh decade of life, with an incidence of one case per million people per year [3]. As an example, in a single institutional experience with 43,000 patients having a monoclonal gammopathy, less than 1 percent had cold-reactive autoantibodies [4].

In the largest reported series to date, covering 89 patients, the median age at diagnosis was 72 years (range: 43 to 91), while the median age at the onset of symptoms was 65 years (range: 41 to 83). Sixty-one percent of the affected individuals were female [4]. In two series, the median survival following diagnosis was 10.6 and 12.5 years, being similar to that of an age- and sex-matched normal population [3,4].


Pathologic cold agglutinins are produced either in response to infection or by paraneoplastic or neoplastic growth of a single lymphocyte clone. In either case, they generally share the same immunochemical characteristics and polysaccharide specificities, and result in the same clinical manifestations.

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Literature review current through: Nov 2017. | This topic last updated: Nov 07, 2017.
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