Cold Agglutinin Disease (CAD)

Cold agglutinin disease (CAD) is classified as an autoimmune hemolytic anemia (AIHA). Cold agglutinins are autoantibodies with an optimum temperature of 3°C to 4°C.1 Cold agglutinins cause symptoms that are due to red cell agglutination in cooler parts of the body and to hemolytic anemia, which develop in affected individuals on exposure to temperatures of 32ºF to 50º F. Patients with classic chronic idiopathic CAD experience clinical symptoms and signs on exposure to cold.1-3 

In the conventional classification, CAD comprises 2 types. Primary, or idiopathic, CAD is not related to any underlying disease; secondary CAD occurs in association with malignant diseases, mainly lymphomas or other cancers; with acute infections;  and with autoimmune disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis.1,4 Secondary CAD can be associated with either monoclonal or polyclonal cold-reacting autoantibodies.2

Genetics and Inheritance 

CAD is not inherited. The cause of the primary type is unknown, and the secondary type is due to or associated with other conditions. In some cases, CAD has been found to be multifactorial in origin, with the involvement of multiple environmental factors and genes. However, disease-causing genes have not been discovered, and familial cases have not been documented.3 The presence of trisomy 3, trisomy 12, and translocation (8;22) has been reported in a few cases in association with CAD.2

Cold Agglutinin Disease
Blood film microscopic view of cold agglutinin disease (CAD), autoimmune hemolytic anemia diagnosis at medical laboratory.
Credit: Getty Images


The main causes of polyclonal secondary CAD are infections due to Mycoplasma pneumoniae and infectious mononucleosis due to Epstein-Barr virus (EBV). The development of transient acute hemolysis can be secondary to these viral infections. Other viral infectious diseases documented to be associated with hemolytic anemia caused by cold agglutinins include cytomegalovirus infection, mumps, varicella, rubella, adenovirus infection, HIV infection, influenza, and hepatitis C. Occasionally, bacterial and parasitic infections have also been implicated, including syphilis, legionnaire disease, listeriosis, malaria, and trypanosomiasis.2

Underlying Malignancy

Causes of monoclonal, secondary CAD are Waldenström macroglobulinemia, lymphomas, chronic lymphoid leukemia, myeloma, and non-hematologic neoplasms.2 The probability that a cold agglutinin-mediated AIHA is associated with an underlying malignancy depends on the age of the patient and the extent to which the case is evaluated. Lymphoid (B-cell or plasma cell) malignancies like aggressive non-Hodgkin lymphoma and Waldenström macroglobulinemia are more frequently found in older (>60 years) than in younger individuals.1 

The association of CAD with plasma cell, B-cell, or lymphoproliferative diseases has been documented in various studies. In a study conducted in 1982 of 78 patients (average age, >60 years) with persistent cold agglutinins, associated lymphoid malignancies were seen in approximately 65%, including lymphomas in 40%, Waldenström macroglobulinemia in 17%, and chronic lymphocytic leukemia (CLL) in 8%.5 

In a case series performed in 2013 involving 89 patients with CAD (median age, 65 years), an underlying hematologic diagnosis was noted in 69 of the patients (78%); among these, monoclonal gammopathy of undetermined significance (MGUS) was seen in 61%, other lymphomas in 12%, unspecified lymphoproliferative disorders in 12%, macroglobulinemia in 9%, and CLL in 6%.6 


Hemolytic anemia in CAD has been documented after living-donor liver transplant in patients treated with tacrolimus and after bone marrow transplant in patients treated with cyclosporine. It has therefore been hypothesized that calcineurin inhibitors, selectively affecting T-cell function and sparing B lymphocytes, can interfere with autoreactive T-cell clone deletions, leading to the development of autoimmune disease.7-9

Autoimmune Disorders

SLE has been found to be associated with some form of AIHA in 3% to 14% of cases and is more prevalent in infants than in adults. AIHA also develops in patients with Sjögren syndrome in 2.8% of cases. Rarely, AIHA develops in patients with inflammatory bowel disease, particularly ulcerative colitis (4.1/100,000 patients).10 CAD has also been documented in patients of systemic sclerosis. The severity of the disease correlates with the degree of anemia, indicating a possible relationship between systemic rheumatic disease and autoimmune hematologic abnormalities.11


  1. Brugnara C, Berentsen S. Cold agglutinin disease. UptoDate. Updated April 22, 2021, Accessed September 6, 2021. 
  2. Aljubran SA. Cold agglutinin disease. Medscape. Updated August 23, 2021. Accessed September 6, 2021.
  3. Cold agglutinin disease. Genetic and Rare Diseases Information Center (GARD), Updated May 26, 2016. Accessed September 6, 2021.
  4. 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.
  5. Crisp D, Pruzanski W. B-cell neoplasms with homogeneous cold-reacting antibodies (cold agglutinins). Am J Med. 1982;72(6):915-922. doi:10.1016/0002-9343(82)90852-x
  6. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-1121. doi:10.1182/blood-2013-02-474437
  7. Kitamura T, Mizuta K, Kawarasaki H, Sugawara Y, Makuuchi M. Severe hemolytic anemia related to production of cold agglutinins following living donor liver transplantation: a case report. Transplant Proc. 2003;35(1):399-400. doi:10.1016/s0041-1345(02)03816-2
  8. Tamura T, Kanamori H, Yamazaki E, et al. Cold agglutinin disease following allogeneic bone marrow transplantation. Bone Marrow Transplant. 1994;13(3):321-323.
  9. Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. 1995;17(6):584-591. doi:10.1097/00007691-199512000-00007
  10. Barcellini W, Giannotta J, Fattizzo B. Autoimmune hemolytic anemia in adults: primary risk factors and diagnostic procedures. Expert Rev Hematol. 2020;13(6):585-597. doi:10.1080/17474086.2020.1754791
  11. Oshima M, Maeda H, Morimoto K, Doi M, Kuwabara M. Low-titer cold agglutinin disease with systemic sclerosis. Intern Med. 2004;43(2):139-142. doi:10.2169/internalmedicine.43.139

Reviewed by Kyle Habet, MD, on 9/8/2021.