DiagnosingCold Agglutinin Disease (CAD)

Understand criteria to accurately diagnose CAD in patients

To diagnose CAD, the following main criteria must be met1,2:

Diagram of stepped process for diagnosing CAD

Patients with AIHA and a DAT positive for C3 IgG should be screened for a cold antibody using a direct agglutination test at room temperature (1C) and should be further investigated with an antibody titer in a laboratory performed on a regular basis (2C). Ethylenediaminetetra-acetic acid-anticoagulated samples should be warmed to 37°C in a water bath for 1 hour prior to removal of the plasma for testing (1C).2

*Alternative causes for hemolytic anemia and a positive DAT may include: HTR, HDN, DIIHA, post transplantation (blood types A, B, AB, and O mismatch or PLS), post IVIg, unrelated cause of hemolytic anemia with an incidental positive DAT.2

Cold Agglutinin Titer detects antibodies that agglutinate red blood cells in cold temperatures.3

The final diagnosis of CAD or mixed AIHA is based on the overall clinical picture, including supportive serological findings.2

§For example, thermal amplitude.2

Recognizing hemolytic biomarkers in patients with CAD

Elevated levels of bilirubin, LDH, and reticulocytes indicate active hemolysis and potential risk for patients with CAD.1,4





Icon of blood representing CAD symptom of hemolytic anemia

The complement
pathway plays a
critical role in CAD

Icon of vein representing CAD risk

CAD can have
serious consequences

AIHA=autoimmune hemolytic anemia; CAD=Cold Agglutinin Disease; DAT=direct antiglobulin test; DIIHA=drug-induced immune hemolytic anemia; HDN=hemolytic disease of the newborn; HTR=hemolytic transfusion reaction; IgG=immunoglobulin G; IVIg=intravenous immunoglobulin; LDH=lactate dehydrogenase; PLS=passenger lymphocyte syndrome.
References: 1. Berentsen S, Tjønnfjord GE. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev. 2012;26(3):107-115. 2. Hill QA, Stamps R, Massey E, et al; on behalf of the British Society for Haematology. The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol. 2017;176(3):395-411. 3. Lab test: cold agglutinin titer level. Evidence-Based Medicine Consult website. https://www.ebmconsult.com/articles/lab-test-cold-agglutinin-titer-level. Accessed October 10, 2019. 4. Barcellini W, Fattizzo B. Clinical applications of hemolytic markers in the differential diagnosis and management of hemolytic anemia. Dis Markers. 2015;2015:1-7. doi:10.1155/2015/635670