Cold Agglutinin Disease (CAD).

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Table of contents

Overview

CAD is a rare, chronic, autoimmune hemolytic anemia with potentially severe acute and chronic consequences caused by C1 activation of the classical complement pathway.1 The prevalence of CAD is estimated to be up to 20 per 1,000,000 people.2-4 The median age of onset of CAD is approximately 60 years, but the disease has also been identified in patients as young as 30 years old.2,5-7 Persistent activation of the classical complement pathway leads to the production of anaphylatoxins, which promotes inflammation. Due to chronic C1-activated hemolysis, many patients remain in a hemolytic state for more than five years.2,9 Episodes of severe anemia are unpredictable and can occur at any time during the disease course.5 CAD is associated with a significantly increased risk of life-threatening thromboembolic events.10 This risk persists regardless of the season.11 The word "cold" in CAD does not refer to weather or season.

Diagnosis

Early recognition of CAD can help patients receive optimal care.¹ CAD is a rare, chronic, autoimmune hemolytic anemia and should not be confused with CAS (cold agglutinin syndrome) secondary to infection or cancer. For patients, CAD is not a benign condition. If CAD is suspected, the blood sample should be kept at 37°C to 38°C from the time of collection until testing to avoid false negative results. Refrigeration should be avoided.


Key steps in the diagnostic algorithm:
Established anemia → Confirmed hemolysis → Positive polyspecific DAT → Clinical assessment → Monospecific DAT positive for C3d → Cold agglutinin titer ≥ 1:64 → Further clinical and serological assessment.

Symptoms 5,7,9,12-15

Symptoms caused by hemolysis:
- Anemia, shortness of breath
- Severe fatigue
- Hemoglobinuria
- Jaundice

Symptoms caused by agglutination:
- Circulatory symptoms: Acrocyanosis, Raynaud's phenomenon
- Livedo reticularis (rarely).

Patients with CAD also have a significantly increased risk of medically treated depression and anxiety.¹⁶

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. 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.
  3. 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
  4. Bylsma LC, Gulbech Ording A, Rosenthal A, et al. Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease. Blood Adv. 2019;3(20):2980-2985. doi:10.1182/bloodadvances.2019000476
  5. 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
  6. 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
  7. 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
  8. Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. 2013;33(6):479-492. doi:10.1016/j.semnephrol.2013.08.001
  9. 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
  10. 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
  11. Kamesaki T, Nishimura J-i, Wada H, et al. Demographic characteristics, thromboembolism risk, and treatment patterns for patients with cold agglutinin disease in Japan. Int J Hematol. 2020;112(3):307-315. doi:10.1007/s12185-020-02899-6
  12. Elharake M, Bors K. Cold agglutinin disease: a case report. W V Med J. 2017;1-4.
  13. 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
  14. 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
  15. Aljubran SA. Cold agglutinin disease clinical presentation. Medscape website. Updated December 2, 2020. Accessed March 30, 2022. emedicine.medscape.com/article/135327-clinical
  16. Patel P, Jiang X, Nicholson G, et al. Medically attended anxiety or depression is increased among newly diagnosed patients with cold agglutinin disease (CAD). Blood. 2020;136(suppl 1):28. doi:10.1182/blood-2020-139791

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