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At a glance

A disorder that is idiopathic or secondary to a malignancy, resulting in immune-hemolytic anemia with exacerbation upon exposure to cold.

Synonyms

Cold Agglutinin Syndrome; Cold Hemagglutinin Disease.

History

First described in 1903 by Karl Landsteiner, an Austrian pathologist and immunologist, who is considered the father of modern transfusion medicine, since he also discovered the ABO system, for which he was awarded the Nobel Prize in 1930.

Incidence

Estimated to be in the range of 1:1,000,000 per year in the general population. It has been estimated that approximately 5 to 20% of all autoimmune hemolytic anemias are caused by cold agglutinins (approximately 1:300,000). No ethnic predilection has been reported; however, females are affected slightly more often than males (1.5:1). All age groups can be affected, although it most often occurs in patients in the seventh decade of life or older and rarely in children. Even in otherwise healthy persons, low cold agglutinin titers (1:64 or less) are common. Significantly higher titers may be associated with infections by Mycoplasma pneumoniae, Legionella, cytomegalovirus, human immunodeficiency virus, influenza virus, Epstein-Barr virus, mumps virus, with malaria, Listeriosis, and trypanosomiasis, but these increased levels are transient and the development of cold agglutinin disease is relatively uncommon, at least in the classic chronic form. While IgM titers above 1:64 are considered abnormal, typically titers greater than 1:1,000 are required for hemolysis to occur at the temperatures reached in the peripheral circulation.

Genetic inheritance

Trisomy 3 has been found in some patients with this disorder. However, cold agglutinin disease is acquired and not inherited.

Pathophysiology

Cold agglutinin disease as a secondary disease is typically associated with a hematologic malignancy (eg, IgM monoclonal gammopathy of undetermined significance [most common], Waldenström macroglobulinemia with production of monoclonal IgM paraprotein, multiple myeloma, lymphomas, Kaposi sarcoma) and infections. Activated B-lymphocytes produce pathogenic antibodies (in about 90% monoclonal IgM, rarely IgA, or IgG directed against the I-antigen of the erythrocyte membrane in adults; rarely the antibodies target the fetal i-antigen). When the blood cools below the “thermal threshold” (approximately 32°C, ie, in acral areas of the body), these giant IgM autoantibodies transiently bind to the red cell membrane and cause red cell agglutination, slugging, and complement binding in peripheral vessels. The IgM molecules then activate the complement cascade and bind C3b to the cell surface. Upon return of these C3b-coated red cells to the warmer central circulation, IgM dissociates. However, the C3b complex remains on the red blood cell, which will then be removed from the circulation by receptor-specific macrophages found mainly in Kupffer cells of the liver (and to a lesser degree in the spleen), leading to extravascular hemolysis and may be some degree of intravascular hemolysis. In severe cases, the red cell-antibody complexes activate the complement system, ...

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