Recognising CAD early can help patients receive optimal care1

CAD is a rare, chronic, autoimmune haemolytic anaemia that shouldn’t be confused with CAS secondary to infection or cancer

Unlike CAS, CAD is not secondary to overt malignancy or an acute infection2,3

CAD icon
  • Chronic cold agglutinin-mediated AIHA*

  • Classical pathway complement-mediated haemolysis

  • Formerly known as primary CAD

CAS icon
  • Cold agglutinin-mediated AIHA secondary to an underlying condition, for example, infections (Mycoplasma pneumoniae or Epstein-Barr virus), rheumatological disorders or overt malignancies
  • Formerly known as secondary CAD

Recognising the clinical manifestations of CAD4-10

C1 activation icon


  • Chronic haemolysis (destruction of RBCs)
  • Anaemia, shortness of breath
  • Profound fatigue
  • Haemoglobinuria
  • Jaundice
Agglutination icon


  • Circulatory symptoms
    – Acrocyanosis
    – Raynaud’s phenomenon
  • Livedo reticularis (rarely)

For patients, CAD is not a benign condition

Confirming a CAD diagnosis2,3,9,11

If CAD is suspected, the test procedure requires the blood sample be kept at 37 °C to 38 °C from the time it is drawn until it is tested to avoid potential false negatives. Refrigeration must be avoided

CAD diagnosis image

C1-activated haemolysis and other consequences are not adequately addressed by current management approaches3,7,11

Current management approaches include cold avoidance, unapproved pharmacotherapies and crisis intervention


Cold avoidance icon

Supportive care with cold avoidance alone often isn’t enough


of patients needed unapproved
pharmacotherapies to manage CAD


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Patients with CAD receive multiple types of unapproved pharmacotherapies


different types, on average


Transfusion icon

Crisis intervention benefit is short lived and inconsistent


key strategies:
• Transfusions
• Plasmapheresis (rare)

AIHA=autoimmune haemolytic anaemia; CAS=cold agglutinin syndrome; DAT=direct antiglobulin test; RBC=red blood cell.

*Patients may have a B-cell lymphoproliferative disorder detectable in blood or marrow but no clinical or radiological evidence of malignancy.
Data from a retrospective analysis of patients with confirmed CAD (n=89).
Data collected from 21 patients who received treatment in a retrospective review of a healthcare database.

References: 1. 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 2. 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 3. Berentsen S, Tjønnfjord GE. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev. 2012;26(3):107-115. doi:10.1016/j.blre.2012.01.002 4. Berentsen S. Complement activation and inhibition in autoimmune hemolytic anemia: focus on cold agglutinin disease. Semin Hematol. 2018;55(3):141-149. doi:10.1053/j.seminhematol.2018.04.002 5. Berentsen S, Röth A, Randen U, Jilma B, Tjønnfjord GE. Cold agglutinin disease: current challenges and future prospects. J Blood Med. 2019;10:93‐103. doi:10.2147/JBM.S177621 6. Elharake M, Bors K. Cold agglutinin disease: a case report. W V Med J. 2017;1-4. 7. Mullins M, Jiang X, Bylsma LC, et al. Cold agglutinin disease burden: a longitudinal analysis of anemia, medications, transfusions, and health care utilization. Blood Adv. 2017;1(13):839-848. doi:10.1182/bloodadvances.2017004390 8. Berentsen S, Randen U, Tjønnfjord GE. Cold agglutinin-mediated autoimmune hemolytic anemia. Hematol Oncol Clin North Am. 2015;29(3):455-471. doi:10.1016/j.hoc.2015.01.002 9. Hill QA, Stamps R, Massey E, Grainger JD, Provan D, Hill A; British Society for Haematology. The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol. 2017;176(3):395-411. doi:10.1111/bjh.14478 10. Aljubran SA. Cold agglutinin disease clinical presentation. Medscape website. Updated December 2, 2020. Accessed March 30, 2022. 11. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-1121. doi:10.1182/blood-2013-02-474437