Cold Agglutinin Disease
What is Cold Agglutinin Disease?
Cold Agglutinin Disease (CAD) is a rare autoimmune hemolytic anemia (destruction of red blood cells) where the immune system mistakenly attacks and destroys red blood cells at low temperatures, typically below 30°C (86°F). The disease is mediated by cold agglutinins, which are primarily IgM autoantibodies. IgM is one of five antibody types that exists as a pentamer in the blood functioning as part of the body’s initial defense system. Peripheral body parts like the extremities, the ears, and the tip of the nose are typically affected. Symptoms tend to worsen during the winter due to cold weather exposure.
Synonyms
- Cold Agglutinin Hemolytic Anemia
- Cold Antibody Hemolytic Anemia
- Cold Antibody Disease
- Cold Autoimmune Hemolytic Anemia
Cold Agglutinin Disease (CAD) is a rare autoimmune hemolytic anemia (destruction of red blood cells) where the immune system mistakenly attacks and destroys red blood cells at low temperatures, typically below 30°C (86°F). The disease is mediated by cold agglutinins, which are primarily IgM autoantibodies. IgM is one of five antibody types that exists as a pentamer in the blood functioning as part of the body’s initial defense system. Peripheral body parts like the extremities, the ears, and the tip of the nose are typically affected. Symptoms tend to worsen during the winter due to cold weather exposure.
CAD has an estimated prevalence of 16 in 1,000,000
In Nordic countries, CAD has an estimated prevalence of 13-16 cases in every 1 million people.
| Name | Abbreviation |
|---|---|
| Cold Agglutinin Hemolytic Anemia | |
| Cold Antibody Hemolytic Anemia | |
| Cold Antibody Disease | |
| Cold Autoimmune Hemolytic Anemia | Cold AIHA |
CAD is caused by autoantibodies, typically IgM, that target red blood cells. In cold conditions, the autoantibodies bind to the “I” or “i” (the fetal form of “I”) carbohydrate antigens found on the surface of all red blood cells. Such binding leads to clumping (agglutination) and destruction of these cells in acral regions of the body including the extremities, the ears, and the tip of the nose. Primary (idiopathic) CAD occurs without any underlying disease and is usually chronic, meaning that it persists over a long period of time with slowly developing symptoms. Secondary CAD is associated with underlying conditions or infections. Lymphoproliferative disorders such as Chronic Lymphocytic Leukemia and lymphomas, especially Non-hodgkin's Lymphoma, are associated with CAD. Fellow autoimmune diseases like Rheumatoid arthritis and Systemic lupus erythematosus (SLE) can cause CAD as well. A number of infectious causes of CAD include Mycoplasma pneumoniae, Epstein-Barr virus (EBV), Cytomegalovirus (CMV), HIV, and Influenza. CAD is not typically inherited, however there may be genetic factors at play. Small scale studies have demonstrated possible involvement of genes KMT2D, CARD11, IGLL5, and CXCR4.
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Fatigue
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Shortness of breath
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Dizziness
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Pale skin
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Jaundice
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Dark urine
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Pain and blue color in fingers/toes upon facing cold (Raynaud's phenomenon)
There are a wide variety of tests that can be taken to diagnose the disorder (https://rarediseases.org/). There’s also a long list of differential diagnoses: Acute anemia, cholangitis, chronic anemia, donath-landsteiner hemolytic anemia, evans syndrome, lymphoproliferative disorders, non-hodgkin lymphoma, systemic lupus erythematosus (SLE), cryoglobulinemia, warm antibody–mediated autoimmune hemolytic anemia (AIHA) - Some cases of cold agglutinin disease may be confused with this condition, particularly those in which the antibody has a high thermal amplitude, episodic hemoglobinuria following cold exposure, neoplasms - especially of the lymphoid type, drug-induced immune hemolytic anemia, rheumatologic diseases manifesting raynaud syndrome, heparin-induced thrombocytopenia/thrombosis syndrome - patients may have painful digits; anemia could be due to bleeding, but other manifestations are different, systemic vasculitis: sometimes with hemolysis (systemic lupus and scleroderma), erythromelalgia in association with primary thrombocythemia and painful fingers and toes, and malaria (http://www.medscape.com/).
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Clinical Evaluation: Assessment of symptoms and physical examination
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Blood tests: signs of hemolysis (low hemoglobin, high bilirubin) and agglutinins
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Coombs Test: positive for C3 complement protein
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Avoid cold exposure
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Rituximab +/- chemotherapy
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Blood transfusion or plasma exchange (acute severe cases)
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Management of underlying disorder
CAD is a chronic condition for which there is no cure. With proper care and treatment, CAD patients can maintain a reasonable quality of life. Mortality attributable directly to Primary CAD is relatively low and patients can expect a near normal life expectancy. Secondary CAD prognosis is closely tied to that of the underlying disorder. Persistent anemia leading to organ involvement has a poorer prognosis. Overall, early recognition and appropriate treatment are key to improving outcomes and minimizing complications, letting patients live full and active lives.
Barcellini, W., & Fattizzo, B. (2024). The evolving management algorithm for the patient with newly diagnosed cold agglutinin disease. Expert Review of Hematology, 17(7), 287–294. https://doi.org/10.1080/17474086.2024.2366540
Berentsen, S. (2016). Cold agglutinin disease. Hematology, 2016(1), 226–231. https://doi.org/10.1182/asheducation-2016.1.226
Carson, J. (2024, October 28). Cold Agglutinin Disease: Practice Essentials, Pathophysiology, Etiology. Medscape.com; Medscape. https://emedicine.medscape.com/article/135327-overview?form=fpf#a4
Cold Agglutinin Disease - Symptoms, Causes, Treatment | NORD. (n.d.). Rarediseases.org. https://rarediseases.org/rare-diseases/cold-agglutinin-disease/#disease-overview-main
Cold Agglutinin Disease Genetics - Rare Disease Advisor. (2021, December 7). Rare Disease Advisor. https://www.rarediseaseadvisor.com/hcp-resource/cold-agglutinin-disease-genetics/
UpToDate. (n.d.). Www.uptodate.com. https://www.uptodate.com/contents/cold-agglutinin-disease
Last updated 10 Feb 2009, 02:05 PM
10 Feb 2009, 02:05 PM
Hi Heather, I also suffer from CAD. I have been treated with prednisone also but more recently with Rituximab which is given by infusion. This has successfully kept my haemoglobin at a better level and more stable. It doesn't work for eveyone but definitely worth a try. You have 1 infusion every week for 4 weeks. Other advice is to really keep warm - don't drink cold drinks or food straight from fridge. Let me know if you want to know more. Best wishes, Katherine
10 Feb 2009, 01:52 PM
My husband has been suffering from what his hematologist calls cold agglutin hemolytic anemia for at least 3 years (at first we thought it was repeated bouts of the flu). Does any one have any advice for slowing down recurrences? Any treatment options besides prednisone? Thanks -- Heather
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Created by heatheratsss | Last updated 10 Feb 2009, 02:05 PM
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