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Cold agglutinin disease
Other Resources UpToDate PubMed

Cold agglutinin disease

Contributors: Nina Haghi MD, Michael W. Winter MD, Benjamin L. Mazer MD, MBA, Paritosh Prasad MD
Other Resources UpToDate PubMed

Synopsis

Cold agglutinin disease (CAD) is an autoimmune disease characterized by cold-sensitive autoantibodies that cause agglutination of RBCs and hemolytic anemia in colder parts of the body. There are 3 causes of CAD: cold agglutinins (which may appear as a primary disease or secondary to an underlying disorder), Donath-Landsteiner antibodies, and cryoglobulins.

Cold agglutinins are usually immunoglobulin M (IgM) antibodies (less commonly IgA or IgG antibodies) that recognize the I antigen (or i antigen in neonates and infants) on RBCs. Primary CAD is sometimes caused by a low-grade clonal bone marrow disorder. It is very rare, with an incidence of about 1 per million in Scandinavian studies. There is a slightly higher prevalence in females, and the median age of diagnosis is approximately 60-70 years, although the range of ages of presentation is very broad (30-90 years). Secondary CAD is due to a viral infection (Epstein-Barr virus [EBV], HIV, influenza, varicella-zoster, or rubella), Mycoplasma pneumoniae infection, autoimmune disease, or lymphoid malignancy. Cold agglutinins cause agglutination of RBCs and extravascular hemolysis.

Donath-Landsteiner antibodies recognize RBC antigens at cold temperatures and fix complement to their surface, causing intravascular hemolysis.

Cryoglobulins are antibodies that form immune complexes and cause vasculitis, vascular occlusion, or systemic inflammatory syndrome.

The presence of cold agglutinins can go unnoticed until the patient is exposed to cold stress. The most common findings include anemia (90% of patients), although of varying degrees of severity and symptomatology, and increased hemolytic markers such as lactate dehydrogenase (LDH), bilirubin, or haptoglobin (90% of patients), but only about half of patients will have cold-induced symptoms (52% in one series but as high as 90% in a series of patients who live in colder climates).

Cold-induced symptoms include:
  • Acrocyanosis (bluish-purple discoloration of fingertips, toes, nose, and ears) is the most common finding.
  • Raynaud phenomenon, a well-demarcated color change of the digits on exposure to cold.
  • Livedo reticularis, a lacy (reticulated), blanching, violaceous rash.
  • Cutaneous ulceration or necrosis.
  • Pain or discomfort swallowing cold food or liquids.

Codes

ICD10CM:
D59.12 – Cold autoimmune hemolytic anemia

SNOMEDCT:
398937006  – Cold autoimmune hemolytic anemia

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Drug Reaction Data

Below is a list of drugs with literature evidence indicating an adverse association with this diagnosis. The list is continually updated through ongoing research and new medication approvals. Click on Citations to sort by number of citations or click on Medication to sort the medications alphabetically.

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References

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Last Reviewed:04/28/2021
Last Updated:04/28/2021
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Cold agglutinin disease
Cold agglutinin disease : Fatigue, Cold agglutinins elevated, Coombs test positive, Cold sensitivity, Anemia
Clinical image of Cold agglutinin disease
Copyright © 2021 VisualDx®. All rights reserved.