What is cold agglutinin disease?

Updated: Aug 28, 2018
  • Author: Salman Abdullah Aljubran, MD; Chief Editor: Michael A Kaliner, MD  more...
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Cold agglutinin disease is a rare form of autoimmune hemolytic anemia caused by cold-reacting autoantibodies. Autoantibodies that bind to the erythrocyte membrane leading to premature erythrocyte destruction (hemolysis) characterize autoimmune hemolytic anemia. (See Pathophysiology and Etiology.) Peripheral blood smears may reveal clumps of red blood cells (RBCs). See the image below.

Peripheral blood smear showing several clumps of R Peripheral blood smear showing several clumps of RBCs with the largest in the center. These are typical of aggregates seen in persons with cold agglutinin disease.

A common complaint among patients with cold agglutinin disease is painful fingers and toes with purplish discoloration associated with cold exposure. In chronic cold agglutinin disease, the patient is more symptomatic during the colder months. See Presentation.

Autoimmune hemolytic anemia is classified as primary or secondary and is subclassified according to autoantibody type. Primary cold agglutinin disease is characterized by a clonal lymphoproliferative disorder. [1, 2] Secondary cold agglutinin syndrome results from a systemic disease—infection or malignancy. [3]

In 90% of cases, the autoantibody in cold agglutinin disease is immunoglobulin M (IgM); rarely, it may involve monoclonal immunoglobulin G (IgG), immunoglobulin A (IgA), or λ light chain restriction. In contrast, warm autoimmune hemolytic anemia predominantly involves IgG. [1]  Donath-Landsteiner hemolytic anemia is also caused by a cold-reacting immunoglobulin, but most cases are due to polyclonal IgG. [1]  

Another autoimmune hemolytic anemia syndrome associated with cold-reacting autoantibodies is paroxysmal cold hemoglobinuria, which involves the IgG Donath-Landsteiner (D-L) antibody. Unlike cold agglutinin disease, in which affected RBCs are removed via extravascular phagocytosis, paroxysmal cold hemoglobinuria involves intravascular hemolysis. (See DDx.)

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