Cold Agglutinin Disease (CAD)

Experts on autoimmune hemolytic anemia (AIHA) convened in November of 2017 in Vienna, Austria, for the First International Consensus Meeting. The goal of the meeting was to summarize current research-based recommendations for the diagnosis and treatment of AIHAs. AIHAs are subdivided into warm and cold types. Cold agglutinin disease (CAD) is the most common type of cold AIHA and accounts for 15% of all cases of AIHA.1 

CAD is a rare autoimmune disease in which cold agglutinins, or antibodies, attack red blood cells upon exposure to cold, causing hemolysis. This process results in AIHA that varies in severity.2

Diagnostic Tests

Experts at the First International Consensus Meeting agreed that a precise diagnostic workup is required because disease progression, therapeutic management, and symptoms depend on the type of antibody involved.3 

The monospecific direct antiglobulin test (DAT), a variant of the Coombs test, is mandatory for the diagnosis of all AIHAs, including CAD.1,3 In this test, a specific globulin is added to a washed sample of erythrocytes taken from a patient. Erythrocyte agglutination after the specific immunoglobulin has been added indicates the presence of AIHA.1 Because the  DAT result can be positive for complement C3 even in the case of a warm AIHA mediated by immunoglobulin M (IgM) autoantibodies, cold agglutinin titration is mandatory for a diagnosis of CAD.4 

Warm and cold AIHAs are differentiated by means of thermal amplitude testing, in which a positive direct anti-globulin test (DAT) result is used to ascertain the optimal temperature for agglutination. In warm AIHAs, the DAT result is  positive at temperatures above 37°C, whereas in cold AIHAs, like CAD, the DAT result is positive at temperatures below 37°C.5,6  

The underlying pathology must be determined, as it will indicate whether a case of CAD is primary or secondary.3 Primary CAD is diagnosed in the absence of an underlying malignancy, autoimmune disorder, or infection; the presence of one of these indicates secondary CAD.7

To determine the severity of CAD-associated hemolytic anemia, a complete blood cell (CBC) count is performed. High values for the mean corpuscular volume (MCV), mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration (MCHC) with a low RBC count are seen in CAD.8 Results of the CBC count, particularly the hemoglobin concentration, will indicate if transfusions are necessary in severe cases with a very low red blood cell count.  

Management of Cold Agglutinin Disease

The management of CAD depends on the severity of the clinical manifestations.9 

Mild Cold Agglutinin Disease

When cold-induced symptoms are mild, avoidance of exposure to cold, including cold beverages and food, and thermal protection with properly layered warm clothing are recommended. It may also be necessary for the patient to wear protective gloves when removing food from the freezer or refrigerator. In most patients with CAD, the hemolytic anemia is mild and active therapy is not required, as it is for those with severe anemia or Raynaud syndrome posing a threat to health or quality of life.9  

Severe Cold Agglutinin Disease

In extreme cases, specially designed protective clothing is required. In secondary CAD, serious symptoms caused by an underlying disorder such as concurrent malignancy or infection require immediate treatment.9

Red blood cell (RBC) transfusion is required in severe, acute anemia.9 Ninety percent of cases of CAD are caused by IgM autoantibodies, and plasmapheresis temporarily reduces the concentration of IgM antibodies in plasma, allowing medications to take effect during emergencies.7,9 

The treatment of CAD differs from that of warm AIHA. Although they are effective in the treatment of warm AIHAs, corticosteroids such as prednisone and splenectomy are typically ineffective for CAD.1,4 Extravascular hemolysis in CAD occurs predominantly in the liver, so that splenectomy is ineffective except in rare cases of IgG-mediated CAD or when the thermal amplitude approaches 37°C.4 

Rituximab (Rituxan®), a monoclonal anti-CD20 antibody, is the most thoroughly researched, best-tolerated first-line treatment for CAD.1,4 Experts at the First International Consensus Meeting reported that recent clinical trial evidence supports a promising combination treatment with rituximab and bendamustine (Treanda®).1,3,4

Sutimlimab (TNT009 and BIVV009) blocked activation of the complement-mediated pathway and the opsonization of erythrocytes by complement C3b in animal studies conducted in vitro.10 Targeting the complement-mediated pathway in CAD was also efficacious in human trials, a finding that indicates sutimlimab is a promising future treatment for patients with CAD.11 

A phase 2 trial of the drug eculizumab (Soliris®) reported a significant reduction in hemolysis and transfusion requirement in patients with CAD.12 Eculizumab acts by binding to the surface of red blood cells, preventing autoantibodies from attacking them in CAD.1


The document published following the First International Consensus Meeting in Vienna outlined various factors that assist in determining the prognosis of a patient with CAD, including thrombogenic factors.1,3 An increased risk for thromboembolic events was discovered in registry-based studies of patients with a diagnosis of CAD.4 A study of severely anemic patients with a diagnosis of CAD before trial enrollment indicated a higher risk for thromboembolic events in this cohort.12 One physician recommends the prophylactic administration of low-molecular-weight heparin or oral anticoagulants to untreated patients with severe anemia or acute exacerbations who have additional risk factors for thrombogenesis.4


  1. Melamed D. Experts share guidelines for diagnosis, treatment of CAD, other AIHAs. News release. Cold Agglutinin Disease News; February 18, 2020.
  2. Smith M. What Is cold agglutinin disease? WebMD. Reviewed December 9, 2019. Accessed September 9, 2021.
  3. 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
  4. Berentsen S. How I treat cold agglutinin disease. Blood. 2021;137(10):1295-1303. doi:10.1182/blood.2019003809
  5. Braunstein EM. Autoimmune hemolytic anemia. Merck Manual Professional Version. Reviewed, revised September 2020. Accessed September 9, 2021.
  6. Thermal amplitude test. Cold Agglutinin Disease News. Updated August 19, 2019. Accessed September 9, 2021.
  7. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-1121. doi:10.1182/blood-2013-02-474437
  8. Aljubran SA. Cold agglutinin disease: workup. Medscape. Updated August 23, 2021. Accessed September 9, 2021.
  9. Aljubran SA. Cold agglutinin disease treatment and management: approach considerations, pharmacologic therapy, transfusions. Medscape. Updated August 23, 2021. Accessed September 9, 2021. 
  10. Shi J, Rose EL, Singh A, et al. TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. Blood. 2014;123(26):4015-4022. doi:10.1182/blood-2014-02-556027
  11. Jäger U, D’Sa S, Schörgenhofer C, et al. Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial. Blood. 2019;133(9):893-901. doi:10.1182/blood-2018-06-856930
  12. Röth A, Bommer M, Hüttmann A, et al. Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Blood Adv. 2018;2(19):2543-2549. doi:10.1182/bloodadvances.2018024190

Reviewed by Kyle Habet, MD, on 9/21/2021.