Cold Agglutinin Disease (CAD)

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA) in which exposure to cold provokes the body’s immune system to attack its own red blood cells, causing them to clump together and eventually leading to their premature destruction (hemolysis).1

Typical Prognosis

CAD typically occurs in older individuals, with a slight predominance among females. One Norwegian study reported the median age of primary CAD patients to be 76 years, with a median age of onset of 67 years, a median survival of about 12.5 years following diagnosis, and a median age of 82 years at death. This analysis suggests that individuals with CAD typically have a life expectancy similar to that of the age-matched general population.2 

Factors Influencing Prognosis

Long-term outcomes are variable, depending on the severity and type of symptoms, underlying cause of the condition, and ability of the affected individual to avoid cold exposure.1 

Primary vs Secondary CAD

Primary CAD is diagnosed in the absence of underlying conditions such as certain malignancies, other autoimmune disorders, or bacterial, viral, or parasitic infections. These underlying causes contribute to the development of secondary CAD. In mild to moderate cases of primary CAD, if excessive cold exposure is avoided, long-term prognosis is good. Individuals with secondary CAD caused by infection have an excellent prognosis, as CAD symptoms typically dissipate within 6 months after the infection has resolved. Individuals with secondary CAD caused by cancers or human immunodeficiency virus (HIV) infection typically have poorer long-term outcomes related to the severity of the underlying condition.1

Severity of Symptoms

The severity of CAD may be influenced by the characteristics of the antigenic specificity of the cold agglutinins. When cold agglutinins attack the Pr antigen system, this may contribute to the development of more severe disease symptoms.3 

Researchers comparing clinical characteristics of patients with differing direct antiglobulin test (DAT) results discovered that DAT-negative individuals had milder symptoms of CAD than those who were DAT-positive.4

Complications of CAD

Complications of CAD include brisk hemolysis caused by cold exposure, severe anemia, ischemic complications in areas of the body exposed to the cold for prolonged periods of time, shock or congestive heart failure caused by severe anemia and hemolysis, and peripheral gangrene after prolonged cold exposure. These severe CAD complications may require prewarmed blood transfusions. The mortality rate of individuals with AIHAs is approximately 10%.3

In a study comparing 608 patients with CAD and 5873 matched controls without CAD, investigators reported that at least 1 thrombotic event occurred in 29.6% of patients with CAD compared to 17.6% of controls. These results indicated that individuals with CAD have an increased likelihood for venous, arterial, and cerebral thrombotic events.5

CAD is a chronic disease that requires daily management, prevention, and, depending on the underlying cause, long-term monitoring. Ordinarily, prognosis is benign, with the exception of individuals who experience recurrent episodes of severe anemia or those with an underlying cause of aggressive B-cell lymphoma.6 

Preventative Measures and Current Treatment Approaches

Preventative measures include layering of clothing when exposed to cold, use of gloves when taking food or beverages out of the freezer or refrigerator, and avoidance of cold food and beverages. Jogging in the cold should be avoided. In general, activities for affected individuals should be less strenuous due to anemia. Diets of individuals affected by CAD should incorporate sources of folic acid, including fresh fruits and vegetables.7

Medications such as antibiotics, antivirals, antiparasitics, and cancer treatments are used to treat underlying causes of secondary CAD. Rituximab is the first-line therapy for CAD. Eculizumab and sutimlimab are also possible treatments, with sutimlimab still awaiting approval from the US Food and Drug Administration (FDA).7

Management of complicated cases of CAD should be overseen by a hematologist-oncologist in collaboration with a blood bank.7


  1. Cold agglutinin disease. Genetic and Rare Diseases Information Center (GARD). Accessed September 22, 2021.
  2. Berentsen S, Beiske K, Tjønnfjord GE. Primary chronic cold agglutinin disease: an update on pathogenesis, clinical features and therapy. Hematology. 2007;12(5):361-370. doi:10.1080/10245330701445392
  3. Aljubran SA. Cold agglutinin disease: prognosis. Medscape. Updated August 23, 2021. Accessed September 22, 2021.
  4. Kamesaki T, Toyotsuji T, Kajii E. Characterization of direct antiglobulin test-negative autoimmune hemolytic anemia: a study of 154 cases. Am J Hematol. 2013;88(2):93-96. doi:10.1002/ajh.23356
  5. Broome CM, Cunningham JM, Mullins M, et al. Increased risk of thrombotic events in cold agglutinin disease: a 10-year retrospective analysis. Res Pract Thromb Haemost. 2020;4(4):628-635. doi:10.1002/rth2.12333
  6. Cold agglutinin disease. Orphanet. Updated August 2010. Accessed September 22, 2021. 
  7. Aljubran SA. Cold agglutinin disease: approach considerations. Medscape. Updated August 23, 2021. Accessed September 22, 2021.

Reviewed by Harshi Dhingra, MD, on 9/23/2021.