Disease Directory Cold Agglutinin Disease
Blood

Cold Agglutinin Disease

Also known as: cold hemagglutinin disease, CAD, cold antibody AIHA

Prevalence

Approximately 1 per million

Onset

Older adults; median age of diagnosis approximately 67-72 years

Type

Acquired (primary or secondary to lymphoproliferative disorder)

About Cold Agglutinin Disease

Cold agglutinin disease is a distinct subtype of autoimmune hemolytic anemia characterized by IgM autoantibodies (cold agglutinins) that bind to I or i antigens on red blood cell surfaces at cold temperatures, leading to complement C3 deposition and subsequent C1-mediated intravascular hemolysis and extravascular hemolysis in the liver. Primary CAD is a clonal lymphoproliferative disorder of the bone marrow producing monoclonal IgM cold agglutinins, while secondary CAD is associated with infections (Mycoplasma pneumoniae, EBV) or lymphoma. Cold temperatures trigger or exacerbate hemolysis, acrocyanosis, and Raynaud-like phenomena, significantly impairing quality of life.

Common Clinical Features

Chronic hemolytic anemia worsened by cold exposure Acrocyanosis and Raynaud phenomenon in cold temperatures Fatigue and pallor from chronic anemia Hemoglobinuria in cold-triggered acute hemolytic episodes Elevated cold agglutinin titer (typically above 1:64 at 4 degrees Celsius) C3-positive but IgG-negative direct antiglobulin test Jaundice and elevated LDH from ongoing hemolysis Livedo reticularis

Clinical Trial Eligibility Tips

What to know before applying to Cold Agglutinin Disease trials.

Cold agglutinin titer (measured at 4 degrees Celsius with monospecific anti-IgM serum) above 1:64 and DAT positive for C3d only (IgG negative) are diagnostic requirements for most CAD trials; bring laboratory documentation from a reference laboratory.

Complement pathway inhibitor trials (targeting C1s, C1q, or C3) are the most active therapeutic area in CAD; prior rituximab response and current hemoglobin level and transfusion frequency determine eligibility.

Bone marrow biopsy documenting underlying clonal lymphoproliferative disorder distinguishes primary CAD from secondary CAD and affects trial eligibility; bring biopsy and immunohistochemistry results.

Patient Resources

Patient Organization

Cold Agglutinin Disease Alliance

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Orphanet

European reference resource for rare diseases (ORPHA:56425)

View on Orphanet ↗

NORD

National Organization for Rare Disorders

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Find recruiting Cold Agglutinin Disease trials

Search 500,000+ studies from ClinicalTrials.gov, filtered for Cold Agglutinin Disease. Updated daily.

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