Cold Agglutinin Disease (CAD)

The mean age of patients presenting with cold agglutinin disease (CAD) is between 67 and 72 years, with a wide range of 30 to 92 years.1,2 However, CAD that develops before the age of 50 is very rare.3 The disease is characterized by the formation of autoantibodies against erythrocyte antigens that are activated at cold temperatures between 3°C and 4°C (37°F-39°F). CAD is 4 times more common in colder climates, and the incidence rates in these regions spike during the winter months.3,4

Clinical Features Overview


Present to some degree in most patients. The median hemoglobin concentration in patients with CAD is approximately 9.3 g/dL.4 The symptoms that accompany anemia may be vague, such as lethargy, weakness, fatigue, dyspnea, reduced exercise tolerance, and syncope. Signs include skin and mucosal pallor, extremities that are cool to the touch, tachypnea, tachycardia, orthostatic hypotension, and systolic flow murmur. In some patients, jaundice secondary to hemolysis may develop.5 Hemolytic anemia may be precipitated by exposure to cold temperatures or by inflammatory responses, and cases range from subclinical to severe anemia requiring transfusion.4 Case reports have described seasonal hemolysis due to weather changes and paradoxical hemolysis due to febrile or other acute illnesses.6,7


Characterized by coolness and a violaceous, dusky discoloration of the acral regions of the body (most common). The ears, nose, lips, and nipples may be involved.8 

Raynaud’s phenomenon (RP)

A common condition characterized by vasospasms in the digits, resulting in decreased blood flow. Common triggers of RP are cold and emotional stress. Clinically, a triphasic color change of the involved digits is accompanied by tingling, numbness, or pain. Initially, the digits turn pale or white, then cyanotic. After blood flow is re-established, the digits become erythematous.9 In severe cases, ulcers, necrosis, or gangrene of the affected digits may develop.10,11

Livedo reticularis

A blue or violaceous, blanchable, patchy, vascular pattern on the skin in a reticular or netlike distribution reflects an underlying change in cutaneous blood flow.12 

Acrocyanosis, RP, and livedo reticularis worsen during exposure to cold and abate after warming. Patients may also endorse odynophagia in reaction to cold foods or liquids.4

Venous thromboembolism (VTE)

Patients with CAD are at increased risk for VTE; at least one VTE occurs in 29.6% of patients with CAD vs 17.6% of patients without CAD (adjusted hazard ratio [aHR], 1.94; 95% CI, 1.64‐2.30).13  Most VTEs occur in the lower extremities and present with pain, swelling, and erythema. The symptoms are usually unilateral. Physical examination typically reveals limb edema, warm skin over the affected area, tenderness, the presence of Homan’s sign, and possible varicosities.14  

CAD should be suspected in patients with autoimmune hemolytic anemia to determine the subtype, especially if the hemolysis and other signs previously described occur in the setting of exposure to cold. Laboratory testing will reveal evidence of hemolysis (high reticulocyte count, high levels of lactate dehydrogenase and indirect bilirubin, and low level of haptoglobin); a positive result of the direct antiglobulin test for C3d; and a cold agglutination titer of 1:64 or higher at 4°C. The latter is highly characteristic of CAD (see section on the diagnosis of CAD).15,16 

Associated Conditions

Cold agglutinin production that is precipitated by infection, autoimmune disease, or lymphoid malignancy is called cold agglutinin syndrome (CAS). Common infections associated with CAS include those caused by Epstein-Barr virus (EBV) and Mycoplasma pneumoniae.17 


Agent that causes infectious mononucleosis, which is characterized by splenomegaly, cervical lymphadenopathy, pharyngitis, headache, intense fatigue, and malaise. Fatigue may persist for several months. Infectious mononucleosis is more common in children and adolescents between the ages of 6 and 19 years.18 

Mycoplasma infection

Many cases are asymptomatic (sometimes referred to as walking pneumonia) and have a gradual onset. Patients generally have a low-grade fever, headache, malaise, and a nagging cough (most prominent feature). Extrapulmonary manifestations include gastrointestinal symptoms, skin rash, erythema nodosum, joint pain, and in severe cases congestive heart failure.19 

It is reasonable to test for autoimmune disorders when a patient presents with arthritis, arthralgias, malar rash, or cytopenias.16  

Other infections associated with CAS include cytomegalovirus infection, hepatitis B, hepatitis C, and HIV infection. Screening for these conditions is recommended in the initial workup of patients with any type of autoimmune hemolytic anemia.16  Tuberculosis (TB) has also been described as a precipitating factor, and screening for TB is recommended by some authors.20 Parvovirus B-19, Treponema pallidum, Brucella, hepatitis A virus, and respiratory syncytial virus have also been described as precipitants in case reports.16 


1. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-1121. doi:10.1182/blood-2013-02-474437

2. Berentsen S, Ulvestad E, Langholm R, Beiske K. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica. 2006;91(4):460-466.

3. Hansen DL, Berentsen S, Fattizzo B, Hansen PL, Barcellini W, Frederiksen H. Seasonal variation in the incidence of cold agglutinin disease in Norway, Denmark, and Italy. Am J Hematol. 2021;96(7):E262-E265. doi:10.1002/ajh.26196

4. Berentsen S, Barcellini W, D’Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. 2020;136(4):480-488. doi:10.1182/blood.2020005674

5. Turner J, Parsi M, Badireddy M. Anemia. StatPearls. 2021. Accessed September 9, 2021.

6. Lyckholm LJ, Edmond MB. Seasonal hemolysis due to cold-agglutinin syndrome. N Engl J Med. 1996;334(7):437. doi:10.1056/NEJM199602153340705

7. Ulvestad E, Berentsen S, Mollnes TE. Acute phase haemolysis in chronic cold agglutinin disease. Scand J Immunol. 2001;54(1-2):239-242. doi:10.1046/j.1365-3083.2001.00960.x

8. Das S, Maiti A. Acrocyanosis: an overview. Indian J Dermatol. 2013;58(6):417-420. doi:10.4103/0019-5154.119946

9. Milam EC, Ramachandran SM, Franks AG Jr. Raynaud phenomenon. JAMA Dermatology. 2015;151(12):1400-1400. doi:10.1001/jamadermatol.2015.0916

10. Iwasaki H. Acronecrosis with cold agglutinin disease mimics diabetic gangrene. Intern Med. 2013;52(7):837-838. doi:10.2169/internalmedicine.52.9313

11. Oh SH, Kim DS, Ryu DJ, Lee KH. Extensive cutaneous necrosis associated with low titres of cold agglutinins. Clin Exp Dermatol. 2009;34(7):e229-e230. doi:10.1111/j.1365-2230.2008.03078.x

12. Rose AE, Sagger V, Boyd KP, Patel RR, McLellan B. Livedo reticularis. Dermatol Online J. 2013;19(12):20705.

13. 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

14. Waheed SM, Kudaravalli P, Hotwagner DT. Deep vein thrombosis. StatPearls. Updated August 11, 2021. Accessed September 9, 2021.

15. Hill QA, Stamps R, Massey E, et al. The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol. 2017;176(3):395-411. doi:10.1111/bjh.14478

16. Jäger U, Barcellini W, Broome CM, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the First International Consensus Meeting. Blood Rev. 2020;41:100648. doi:10.1016/j.blre.2019.100648

17. Berentsen S. How I treat cold agglutinin disease. Blood. 2021;137(10):1295-1303. doi:10.1182/blood.2019003809

18. Hoover K, Higginbotham K. Epstein Barr virus. StatPearls. Updated August 11, 2021. Accessed September 9, 2021.

19. Abdulhadi B, Kiel J. Mycoplasma pneumonia. StatPearls. Updated July 25, 2021. Accessed September 9, 2021.

20. 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

Reviewed by Harshi Dhingra, MD, on 9/21/2021.