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  3. Cold agglutinin disease
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Cold agglutinin disease


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Other Names:
Anemia, hemolytic, cold antibody; Cold antibody hemolytic anemia; Cold antibody disease; Anemia, hemolytic, cold antibody; Cold antibody hemolytic anemia; Cold antibody disease; CAD See More
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Blood Diseases
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Summary Summary


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Cold agglutinin disease is a rare type of autoimmune hemolytic anemia in which the body's immune system mistakenly attacks and destroys its own red blood cells. When affected people's blood is exposed to cold temperatures (32º to 50º F), certain proteins that normally attack bacteria (IgM antibodies) attach themselves to red blood cells and bind them together into clumps (agglutination). This eventually causes red blood cells to be prematurely destroyed (hemolysis) leading to anemia and other associated signs and symptoms. Cold agglutinin disease can be primary (unknown cause) or secondary, due to an underlying condition such as an infection, another autoimmune disease, or certain cancers. Treatment depends on many factors including the severity of the condition, the signs and symptoms present in each person, and the underlying cause.[1][2][3]
Last updated: 5/26/2016

Symptoms Symptoms


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Symptoms of cold agglutinin disease (CAD) are often triggered or made worse by cold temperatures or a viral infection. Therefore, symptoms generally are worse during winter months. Symptoms may arise suddenly or gradually.[4]

Most people with CAD have symptoms of hemolytic anemia (destruction of red blood cells, causing low levels of red blood cells).[5] However, the number of symptoms and severity of symptoms may depend on how severe the anemia is. Signs and symptoms of hemolytic anemia may include:[2][4][5][6]
  • Tiredness (fatigue).
  • Dizziness.
  • Headaches.
  • Cold hands and feet.
  • Pale skin.
  • Dark urine.
  • Jaundice.
  • Chest pain.
  • Pain in the back or legs.
  • Vomiting or diarrhea.
  • Heart problems such as an irregular heartbeat (arrhythmia), a heart murmur, an enlarged heart, or heart failure. These may occur because the heart has to work harder to make sure the body gets enough healthy red blood cells.
Many people with CAD also experience pain and bluish coloring of the hands and feet (acrocyanosis) or Raynaud's disease.[1][5][7] These symptoms result from slow or poor circulation and can range from mild to disabling.[5]

Other signs and symptoms of CAD may include enlargement of the spleen (splenomegaly) and mottled discoloration of the skin (livedo reticularis).[2][4][7]

In people with secondary CAD (associated with another underlying condition), there may be additional signs and symptoms depending on the condition present. For example:[1]
  • Mycoplasma pneumoniae infection (the most common cause of secondary CAD) may cause respiratory symptoms.
  • Various infections or cancers may cause enlarged or swollen lymph nodes.
Last updated: 12/18/2017

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing of 14 |
Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Arthralgia
Joint pain
0002829
Autoimmunity
Autoimmune disease
Autoimmune disorder
[ more ]
0002960
Fatigue
Tired
Tiredness
[ more ]
0012378
Hemolytic anemia 0001878
Muscle weakness
Muscular weakness
0001324
Pallor 0000980
5%-29% of people have these symptoms
Abnormal urinary color
Abnormal urinary colour
Abnormal urine color
[ more ]
0012086
Back pain 0003418
Diarrhea
Watery stool
0002014
Headache
Headaches
0002315
Hepatomegaly
Enlarged liver
0002240
Lymphadenopathy
Swollen lymph nodes
0002716
Nausea and vomiting 0002017
Splenomegaly
Increased spleen size
0001744
Showing of 14 |
Do you have more information about symptoms of this disease? We want to hear from you.
Last updated: 2/1/2021

Cause Cause


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Cold agglutinin disease is typically classified as primary (unknown cause) or secondary (caused by an underlying condition). Secondary cold agglutinin disease may be associated with:[1][3]
  • Bacterial Infections such as mycoplasma, Legionnaires' disease, syphilis, listeriosis, or E. Coli
  • Viral infections such Epstein-Barr virus, cytomegalovirus, mumps, varicella, rubella, adenovirus, HIV, influenza, or hepatitis C
  • Parasitic infections such as malaria or trypanosomiasis
  • Other autoimmune diseases such as systemic lupus erythematosus
  • Certain types of cancers such as lymphoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, multiple myeloma, and Kaposi sarcoma
Last updated: 5/26/2016

Inheritance Inheritance


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Cold agglutinin disease is not an inherited condition. It is designated as either primary (unknown cause) or secondary (associated with or caused by another condition). In some cases, cold agglutinin may be multifactorial which means that multiple environmental factors and genes likely interact to predispose a person to developing the condition.[4] However, to our knowledge, no disease-causing genes have been identified and no familial cases have been reported.
Last updated: 5/26/2016

Diagnosis Diagnosis


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A diagnosis of cold agglutinin disease may be made after several types of tests are performed by a health care provider. In some cases, the diagnosis is first suspected by chance if a routine complete blood count (CBC) detects abnormal clumping (agglutination) of the red blood cells. In most cases, the diagnosis is based on evidence of hemolytic anemia (from symptoms and/or blood tests). A person may also be physically examined for spleen or liver enlargement. An antiglobulin test (called the Coombs test) may be performed to determine the presence of a specific type of antibody. In people with cold agglutinin disease, the Coomb's test is almost always positive for immunoglobulin M (IgM).[1][2]

Detailed information about the various tests used to make a diagnosis of cold agglutinin disease is available on Medscape Reference's website. Please click on the link to access this resource.
Last updated: 5/26/2016

Treatment Treatment


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The treatment of cold agglutinin disease depends on many factors including the severity of the condition, the signs and symptoms present in each person, and the underlying cause. For example, in those affected by secondary cold agglutinin disease, it is important to diagnose and treat the underlying condition which may include certain types of cancer; bacterial, viral, or parasitic infections; and/or other autoimmune disease. People with few symptoms and/or mild anemia may not require any specific treatment. These cases are often managed by simply avoiding exposure to the cold. [3][8]

In severe cases of hemolysis, medical interventions may be necessary. Rituximab (an antibody that selectively reduces specific types of immune cells) is effective in about 60% of cases of severe cold agglutinin disease. Medical researchers have found the response to rituximab is seen on average within 1 to 2 months of treatment and the effect of the treatment lasts for about 1 to 2 years. Rituximab may be used after a second and even a third relapse, however the success rate is less. Combined treatment with rituximab and fludarabine has resulted in higher response rates (76% of cases) and longer periods of remissions (on average, 6.5 years). However the combined treatment may include serious side effects so is presently only recommended when rituximab has not worked alone. Finally, plasmapheresis, which involves filtering blood to remove antibodies, may be useful in acute hemolytic crisis and before surgery requiring hypothermia, however its effect is only short term. It should be noted, removing the spleen is not recommended for cold agglutinin disease.  In addition, because severe cold agglutinin disease requires very high doses of corticosteroids (levels not considered safe), corticosteroid treatment is no longer a recommended treatment in severe cases.[3][8]

Several possible therapies have been reported in a few case reports to have successfully treated people who are not responding to the treatments listed above.[3][8] However more studies need to be performed before the safety and effectiveness of these therapies can be determined.  Click the link to view the therapies presently being studied in cold agglutinin clinical trials. 
Last updated: 5/26/2016

Prognosis Prognosis


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The long-term outlook (prognosis) for people with cold agglutinin disease varies based on many factors including the severity of the condition, the signs and symptoms present in each person and the underlying cause. For example, people with cold agglutinin disease caused by bacterial or viral infections tend to have an excellent prognosis; in these cases, the symptoms typically disappear within 6 months after the infection has resolved. Mild to moderate primary (unknown cause) cold agglutinin disease can also be associated with a good prognosis if excessive exposure to the cold is avoided. Those with cold agglutinin disease caused by HIV infection or certain types of cancer generally have a poor prognosis due to the nature of the underlying condition.[1]
Last updated: 5/26/2016

Statistics Statistics


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Cold agglutinin disease most commonly affects adults who are of middle age and older. Some studies also report a slight bias in favor of females in the incidence of cold agglutinin disease, particularly in older populations. People with infectious mononucleosis, lymphoproliferative diseases, or mycoplasma pneumonia are more susceptible to this condition.[1][2][3]
Last updated: 5/26/2016
Do you have updated information on this disease? We want to hear from you.

Related Diseases Related Diseases


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Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
The differential diagnosis for cold agglutinin disease is mixed AIHA (see this term).
Visit the Orphanet disease page for more information.

Research Research


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Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • ClinicalTrials.gov lists trials that are related to Cold agglutinin disease. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

    Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.

Patient Registry

  • The Autoimmune Registry supports research for Cold agglutinin disease by collecting information about patients with this and other autoimmune diseases. You can join the registry to share your information with researchers and receive updates about participating in new research studies. Learn more about registries.

Organizations Organizations


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Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

  • Cold Agglutinin Disease Foundation (CADF)
    1874 E. State, Suite 4
    Cherry Hill, NJ 08003
    E-mail: info@cadfadvocacy.org
    Website: https://coldagglutinindisease.org

Social Networking Websites

  • Visit the following Facebook groups related to Cold agglutinin disease:
    Cold Agglutinin Disease Foundation Chat

Organizations Providing General Support

  • American Autoimmune Related Diseases Association (AARDA)
    19176 Hall Road, Suite 130
    Clinton Township, MI 48038
    Toll-free: 800-598-4668
    Telephone: 586-776-3900
    Fax: 586-776-3903
    E-mail: aarda@aarda.org
    Website: https://www.aarda.org/
Do you know of an organization? We want to hear from you.

Learn More Learn More


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These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • The Merck Manual provides information on this condition for patients and caregivers. 
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

  • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
  • The Merck Manual for health care professionals provides information on Cold agglutinin disease.
  • MeSH® (Medical Subject Headings) is a terminology tool used by the National Library of Medicine. Click on the link to view information on this topic.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Cold agglutinin disease. Click on the link to view a sample search on this topic.

News & Events News & Events


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News

  • Rare Disease Day at NIH 2021
    March 1, 2021

GARD Answers GARD Answers


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Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.

Have a question? Contact a GARD Information Specialist.

References References


  1. Aljubran SA. Cold Agglutinin Disease. Medscape Reference. April, 2015; http://emedicine.medscape.com/article/135327-overview.
  2. Anemia, Hemolytic, Cold Antibody. National Organization for Rare Disorders (NORD). 2006; http://rarediseases.org/rare-diseases/anemia-hemolytic-cold-antibody/.
  3. Schrie SL, Rosse WF. Clinical features and treatment of autoimmune hemolytic anemia: Cold agglutinins. UpToDate. Waltham, MA: UpToDate; September 11, 2015; http://www.uptodate.com/contents/clinical-features-and-treatment-of-autoimmune-hemolytic-anemia-cold-agglutinins.
  4. Michel M. Cold agglutinin disease. Orphanet. August, 2010; http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=56425.
  5. Berentsen S, Randen U, Tjønnfjord GE. Cold agglutinin-mediated autoimmune hemolytic anemia. Hematol Oncol Clin North Am. June, 2015; 29(3):455-471. https://www.ncbi.nlm.nih.gov/pubmed/26043385.
  6. Hemolytic anemia. National Heart, Lung, and Blood Institute (NHLBI). https://www.nhlbi.nih.gov/health-topics/hemolytic-anemia. Accessed 12/18/2017.
  7. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. August 15, 2013; 122(7):1114-1121. http://www.bloodjournal.org/content/122/7/1114?sso-checked=true.
  8. Barcellini W. Current treatment strategies in autoimmune hemolytic disorders. Expert Rev Hematol. October 2015; 8(5):681-91. http://www.ncbi.nlm.nih.gov/pubmed/26343892.
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