Cold agglutinin disease

Cold agglutinin disease
Cold agglutination - at body temperature, the antibodies do not attach to the red blood cells. At lower temperatures, however, the antibodies react to Ii antigens, bringing the red blood cells together, a process known as agglutination
Classification and external resources
Specialty	hematology
ICD-10	D59.1
ICD-9-CM	283.0
DiseasesDB	2949
eMedicine	med/408
MeSH	D000744

Cold agglutinin disease is an autoimmune disease characterized by the presence of high concentrations of circulating antibodies, usually IgM, directed against red blood cells.^[1] It is a form of autoimmune hemolytic anemia, specifically one in which antibodies only bind red blood cells at low body temperatures, typically 28-31 °C.

It was first described in 1957.^[2][3]

Etiology

There are two forms of cold agglutinin disease: 1-primary and 2-secondary.

• The primary form is by definition idiopathic, a disease for which no cause is known.^[4]

• Secondary cold agglutinin disease is a result of an underlying condition.
  • In adults, this is typically due to a lymphoproliferative disease such as lymphoma and chronic lymphoid leukemia, or infection. Waldenström's macroglobulinemia may also be positive for cold agglutinins.
  • In children, cold agglutinin disease is often secondary to an infection, such as Mycoplasma pneumonia, mononucleosis, and HIV.

Pathophysiology

All individuals have circulating antibodies directed against red blood cells, but their concentrations are often too low to trigger disease (titers under 64 at 4 °C). In individuals with cold agglutinin disease, these antibodies are in much higher concentrations (titers over 1000 at 4 °C).

At body temperatures of 28-31 °C, such as those encountered during winter months, and occasionally at body temperatures of 37 °C, antibodies (generally IgM) bind to the polysaccharide region of glycoproteins on the surface of red blood cells (typically the I antigen, i antigen, and Pr antigens). Binding of antibodies to red blood cells activates the classical pathway of the complement system. If the complement response is sufficient, red blood cells are damaged by the membrane attack complex, an effector of the complement cascade. In the formation of the membrane attack complex, several complement proteins are inserted into the red blood cell membrane, forming pores that lead to membrane instability and intravascular hemolysis (destruction of the red blood cell within the blood vessels).

If the complement response is insufficient to form membrane attack complexes, then extravascular lysis will be favored over intravascular red blood cell lysis. In lieu of the membrane attack complex, complement proteins (particularly C3b and C4b) are deposited on red blood cells. This opsonization enhances the clearance of red blood cell by phagocytes in the liver, spleen, and lungs, a process termed extravascular hemolysis.

Individuals with cold agglutinin disease present with signs and symptoms of hemolytic anemia. Those with secondary agglutinin disease may also present with an underlying disease, often autoimmune.

Treatment

• Avoid cold weather.
• Treat the underlying lymphoma.
• No cold drinks; all drinks should be at normal temperature.
• Requires Heater to maintain temperature in cold places.

Treatment with rituximab has been described.^[5]

See also

• Warm antibody autoimmune hemolytic anemia
• List of hematologic conditions

References