Cold agglutinin disease
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Synopsis
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 often associated with lymphoproliferative bone marrow disorders. 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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Diagnostic Pearls
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Differential Diagnosis & Pitfalls
- Warm autoimmune hemolytic anemia
- Drug-induced hemolytic anemia (antibiotics, NSAIDs, antimalarials)
- Paroxysmal nocturnal hemoglobinuria
- Transfusion reaction
- Other anemias (eg, iron deficiency anemia)
- Glucose-6-phosphate dehydrogenase deficiency
- Myeloproliferative disease
- Microangiopathic hemolytic anemia
- Hypersplenism
- Thalassemia (eg, alpha thalassemia, beta thalassemia)
- Lead poisoning
- Porphyria (eg, porphyria cutanea tarda)
- Aplastic anemia
- Myelodysplastic syndrome
- Infection (malaria, mononucleosis, babesiosis, etc)
- Biliary obstruction (cirrhosis, cholangitis, hepatobiliary malignancy)
- Thrombotic thrombocytopenic purpura / hemolytic uremic syndrome
- HELLP syndrome
- Hereditary spherocytosis and other RBC membrane defects
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Management Pearls
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Therapy
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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.Subscription Required
References
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Last Reviewed:04/28/2021
Last Updated:03/20/2023
Last Updated:03/20/2023
Cold agglutinin disease