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Disease Profile

Cold agglutinin disease

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 1 000 000

331 - 2,979

US Estimated

1-9 / 1 000 000

514 - 4,622

Europe Estimated

Age of onset

Adult

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ICD-10

D59.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Anemia, hemolytic, cold antibody; Cold antibody hemolytic anemia; Cold antibody disease;

Categories

Blood Diseases

Summary

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]

Symptoms

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]

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.

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

Cause

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]

Diagnosis

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.

Treatment

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.

Organizations

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

    Social Networking Websites

      Organizations Providing General Support

        Learn more

        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.

            References

            1. Aljubran SA. Cold Agglutinin Disease. Medscape Reference. April, 2015; https://emedicine.medscape.com/article/135327-overview.
            2. Anemia, Hemolytic, Cold Antibody. National Organization for Rare Disorders (NORD). 2006; https://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; https://www.uptodate.com/contents/clinical-features-and-treatment-of-autoimmune-hemolytic-anemia-cold-agglutinins.
            4. Michel M. Cold agglutinin disease. Orphanet. August, 2010; https://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. https://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. https://www.ncbi.nlm.nih.gov/pubmed/26343892.

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