Cold Agglutinin Disease (CAD)

CAD is a severe, chronic, rare blood disorder.1 It is a type of autoimmune hemolytic anemia (AIHA), which means that the body’s immune system attacks and destroys its own red blood cells by mistake.2

Symptoms of CAD may include fatigue, dizziness, chest pain, shortness of breath, anemia, transfusion requirements, dark urine and increased risk of thrombotic events like stroke or heart attack.2

In people with CAD, autoantibodies such as immunoglobin M (IgM) cause red blood cells to clump together when extremities (nose, ears, fingers, toes) are exposed to cold temperatures or when an individual with CAD has a compromised immune system or infection.3 Then, the complement cascade, which plays an important role in the immune system, is activated to destroy heathy red blood cells in a process called hemolysis.4,5

Excessive activation of the complement cascade can lead to the onset or progression of many diseases including CAD.6,7


  1. Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis: an 18-year study of 865 cases referred to a regional transfusion centre. Br Med J (Clin Res Ed). 1981;282(6281):2023-2027.
  2. National Institute of Health (NIH), Genetic and Rare Diseases Information Center (GARD) Website Accessed November 21, 2019.
  3. Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica. 2006;91(4):460-466.
  4. Cold agglutinin disease. Genetic and Rare Diseases Information Center Web site. Accessed November 21, 2019.
  5. Reynaud Q, Durieu I, Dutertre M, et al. Efficacy and safety of rituximab in auto-immune hemolytic anemia: A meta-analysis of 21 studies. Autoimmun Rev. 2015;14(4):304-313.
  6. Morgan P, et al. Complement, a target for therapy in inflammatory and degenerative diseases. Nature Reviews Drug Discovery. 2015;14:857-877.
  7. Markiewski MM, Lambris JD. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol. 2007;171(3):715-727.

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