Cold Agglutinin Disease (CAD)

Overview

An uncommon autoimmune condition known as Cold Agglutinin Disease (CAD) is defined by the presence of large amounts of circulating IgM-type autoantibodies and cold-sensitive antibodies that attack red blood cells and cause them to agglutinate and undergo lysis. It is a special type of autoimmune hemolytic anemia where antibodies only bind red blood cells at low body temperatures, usually between 28 and 31 °C.

Red blood cells from affected individuals clump together when their blood is subjected to freezing temperatures (between 32 °F (0 °C; 273 K) and 50 °F (10 °C; 283 K). These proteins, known as IgM antibodies, ordinarily assault microorganisms (agglutination). Hemolysis the eventual premature destruction of red blood cells leads to anemia and various related signs and symptoms.

Cold agglutinin illness might have an underlying condition such as an infection, another autoimmune disease, or specific tumors as a primary (unknown origin) cause or secondary (caused by the underlying condition). The severity of the condition, the symptoms experienced by each individual, and the underlying cause are just a few of the variables that affect how to proceed with treatment.

In 1957, the first case of cold agglutinin disease was reported.

History

Landsteiner originally described cold hemagglutination in 1903, and it was discovered in humans in 1918. In 1937, Rosenthal and Corten wrote about how cold hemagglutination and hemolysis are related. Dacie and Schubothe provided comprehensive accounts of 16 CAD patients each in the 1960s. Cold agglutinins (CA), the autoantibodies that cause hemagglutination at low temperatures, can be discovered in the sera of both healthy individuals and patients with AIHA of the cold reactive varieties. At a temperature of 0 to 4 °C, CA binds to erythrocyte surface antigens most effectively. Monoclonal CA frequently has a high-thermal amplitude, which contributes to their pathogenicity at temperatures around 37 °C, in contrast to polyclonal CA in healthy individuals.

Erythrocytes become agglutinated when CA is bound, and the antigen-antibody complex also triggers complement (C) activation and hemolysis. Hemolytic anemia and circulatory symptoms brought on by colds are important clinical indications of primary CAD. However, until recently, precise estimates of the severity of anemia and the frequency of symptoms brought on by colds were not available.

Physiology

All people have circulating antibodies that target red blood cells, but their levels are frequently insufficient to cause disease (titers under 64 at 4 °C). These antibodies are present in much higher concentrations (titers over 1000 at 4 °C) in people with cold agglutinin disease.

Antibodies (usually IgM) bind to the polysaccharide area of glycoproteins on the surface of red blood cells at body temperatures of 28-31 °C, such as those experienced during the winter, and occasionally at body temperatures of 37 °C (typically the I antigen or Pr antigen). Antibodies attaching to red blood cells cause the complement system's traditional route to being activated. The membrane assault complex, an effector of the complement cascade, damages red blood cells if the complement response is sufficient. Multiple complement proteins are inserted into the red blood cell membrane during the development of the membrane assault complex, creating holes that cause membrane instability and intravascular hemolysis (destruction of the red blood cell within the blood vessels).

Extravascular lysis will be preferred over intravascular red blood cell lysis if the complement response is insufficient to produce membrane assault complexes. Complement proteins, in particular C3b and C4b, are deposited on red blood cells in place of the membrane assault complex. Extravascular hemolysis, a process where red blood cells are cleared by phagocytes in the liver, spleen, and lungs, is made possible by this opsonization.

Hemolytic anemia symptoms and indicators are evident in those with cold agglutinin illness. Patients with secondary agglutinin disease may also have an underlying illness, frequently an autoimmune condition.

Diagnosis

A direct Coombs antiglobulin test looks for antibodies (cold or warm) and/or the complement system on the patient's RBC. An indirect Coombs antiglobulin test looks for antibodies in the patient's serum, which are still circulating in the blood and have not yet formed any complexes with RBC.

A doctor may conduct various tests before determining whether a patient has cold agglutinin sickness. When a routine complete blood count (CBC) reveals abnormal red blood cell clumping (agglutination), the diagnosis may initially be suspected by accident. The majority of the time, blood tests and/or symptoms that indicate hemolytic anemia are used to make the diagnosis. Physical examinations can also check for enlarged liver or spleen.

Physical examinations can also check for enlarged liver or spleen. To ascertain the presence of a particular kind of antibody, an antiglobulin test, also known as the Coombs test, may be conducted. The Coombs test for immunoglobulin M is almost always positive in people with cold agglutinin disease.

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