Causes of Cold Agglutinin Disease

Cold agglutinin disease (CAD) is a rare autoimmune disorder characterized by autoantibodies, called cold agglutinins, binding to and activating the destruction of red blood cells (RBCs) when exposed to cold temperatures.

How cold agglutinins cause CAD

CAD can manifest as a primary or a secondary disease. In both these CAD types, the cold agglutinins bind to RBCs when exposed to cold temperatures and activate the classical complement pathway, which then targets these blood cells for destruction by other components of the immune system.

The excessive destruction of the RBCs causes hemolytic anemia (low hemoglobin levels), which gives rise to such characteristic symptoms of CAD as excessive fatigue, weakness, jaundice, and joint pain.

Cold agglutinins in primary and secondary CAD

Primary CAD

The production of cold agglutinins in primary CAD is attributed to B-cell lymphoproliferative disease, or blood disorders involving the uncontrolled growth of lymphocytes (white blood cells). B-cells are immune cells that produce antibodies when exposed to various antigens, or foreign invaders like toxins, bacteria and viruses.

In the case of primary CAD, cold agglutinin antibodies, mostly of the IgM type, are generated. (IgM type antibodies are proteins that typically attack bacteria.)

The B-cell lymphoproliferative disease associated with primary CAD does not develop into cancers like myeloma or lymphoma. Primary CAD is a chronic condition that will persist and require constant care and treatment.

Secondary CAD

Secondary CAD is the result of an underlying primary disease such as bacterial, viral or parasitic infections, another autoimmune disease, or a lymphoid malignancy such as lymphoma. The primary disease causes the production of cold agglutinins. Secondary CAD is mostly transient and, in most cases, treating the primary disease will resolve CAD.


Cold agglutinins can be produced during various bacterial, viral, and parasitic infections.

Autoimmune disorders

Autoimmune disorders such as scleroderma, rheumatoid arthritis, and systemic lupus erythematosus are associated with secondary CAD.

Lymphoid malignancies

Lymphoid malignancies are cancers of the lymphatic system that works to protect the body against infection; it includes the lymph nodes, spleen and bone marrow.  Lymphoid cancers, such as lymphoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), and Kaposi sarcoma, are associated with secondary CAD.


Last updated: August 14, 2019


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