Causes of CAD

Cold agglutinin disease (CAD) is caused by the body’s immune system erroneously attacking and destroying red blood cells — the cells that carry oxygen through the bloodstream. CAD is a type of autoimmune hemolytic anemia (AIHA), a broad category of diseases in which the body’s immune system wrongly targets and destroys red blood cells.

In CAD, this attack on red blood cells is driven by the presence of self-reactive antibodies called cold agglutinins.

What are cold agglutinins?

Antibodies are specialized proteins made by the immune system that normally help defend the body against disease-causing invaders like infectious bacteria. Sometimes, however, the immune system erroneously makes antibodies that target the body’s own healthy tissues.

Cold agglutinins are one such type of self-targeting antibody, or autoantibody. Most cold agglutinins are a particular form of an antibody called immunoglobulin M, or IgM.

At cold temperatures — 32 to 50 F, or 0 to 10 C — cold agglutinins bind to red blood cells, causing them to clump together. This process is called “agglutination,” and it ultimately leads to the premature destruction of red blood cells and, consequently, to anemia and other disease symptoms.

Cold agglutinins also can prompt other components of the immune system, particularly the complement cascade, to destroy red blood cells.

Primary vs. secondary CAD

Based on the underlying cause, CAD can be classified as either primary or secondary. When CAD occurs in the context of another overt disease, such as cancer or an infection, it is considered secondary. By contrast, primary CAD occurs in the absence of any other known health condition.

Causes of primary CAD

B-cells are the immune cells that make cold agglutinins and other types of antibodies. Each B-cell can make only one single type of antibody. When a B-cell divides, its daughter cells can still make only that particular type of antibody.

It is thought that primary CAD develops when B-cells that make cold agglutinins start to divide more than normal.

Causes of secondary CAD

In up to 70% of cases, CAD is associated with an underlying disorder, including several infectious diseases, cancers, and other autoimmune diseases.

Viral infections associated with secondary CAD include Epstein-Barr virus, cytomegalovirus, mumps, varicella, rubella, adenovirus, HIV, influenza, and hepatitis C. Bacterial infections that have been linked to secondary CAD include mycoplasma, Legionnaires’ disease, syphilis, listeriosis, or E. Coli.

Secondary CAD also can develop due to parasitic infections like malaria or trypanosomiasis (Chagas disease), or due to other autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

Secondary CAD also may develop in association with certain cancers, especially blood cancers like lymphoma, leukemia, and multiple myeloma.


CAD is not hereditary, which means it cannot be passed from parents to their biological children.

Nevertheless, some evidence suggests there are genetic alterations in B-cells that produce cold agglutinins, which drive the disease. Research has indicated that, in people with CAD, these B-cells often have mutations in two genes called KMT2D and CARD11. Another study suggested that certain chromosomal abnormalities are common in cold agglutinin-producing B-cells.


Last updated: Sept. 28, 2021


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