Cold Agglutinin Disease

Diagnostic Algorithm

Clinical Background

Cold agglutinin disease is a form of autoimmune hemolytic anemia caused by cold-reacting antibodies and is classified as either primary (idiopathic) or secondary.

Epidemiology

• Incidence – <1/100,000 in U.S.
• Age – onset is >60 years; most common ≥70 years
• Sex – M:F, equal 
  • Some report a slight female predominance in older populations

Classification

• Primary cold agglutinin disease
  • Usually associated with monoclonal cold-reacting autoantibodies
• Secondary cold agglutinin disease
  • May be associated with either monoclonal or polyclonal cold-reacting autoantibodies
  • Predominantly caused by infection and lymphoproliferative disorders
  • Usually transient in children and young adults

Risk Factors

• Lymphoproliferative disorders
  • Chronic lymphocytic leukemia (CLL)
  • Non-Hodgkin lymphomas
  • Hodgkin disease
  • Monoclonal gammopathy of undetermined significance (MGUS)
• Primary infection
  • Mycoplasma pneumonia
  • Influenza A and B
  • Adenoviral illness
  • Mononucleosis
  • Malaria
• Genetic
  • Mutations – Trisomy 3 and 12
• Autoimmune disorders
  • Systemic lupus erythematosus (SLE)
  • Systemic sclerosis (scleroderma)
  • Antiphospholipid syndrome (APS)
  • Ulcerative colitis

Pathophysiology

• Termed "cold agglutinin" because they cause affected human red blood cells to agglutinate at 4ºC
• Cold-reacting autoantibodies are usually IgM, occasionally IgG, and rarely IgA
  • May be polyclonal, with the presence of kappa and lambda light chains
  • May also be monoclonal with a single type of light chain, usually kappa
• Immunoglobulin-mediated deposition of complement on red blood cell membranes

Clinical Presentation

• Hemolytic anemia is often the sole manifestation
• Dermatologic – acrocyanosis, Raynaud phenomenon, livedo reticularis
• Chronic cold agglutinin disease is rare
• May present as part of a paraneoplastic syndrome

Diagnosis

• Indications for testing – hemolytic anemia, particularly in presence of lymphoproliferative disorder
• Laboratory testing
  • Indications of hemolysis are positive (hyperbilirubinemia, increased LDH)
  • CBC with peripheral smear – demonstrates anemia and hemolysis
  • Reticulocyte count – elevated
  • DAT specific for C3d and IgG usually positive; establishes the presence of immunoglobins and complement degradation products on RBC surface
    • Positive test alone does not establish autoimmune hemolytic anemia; 0.007-0.01% of normal population is positive
  • Serum cold agglutinin testing
    • Low levels may also be found in healthy adults and those with peripheral vascular disease or nonlymphoid neoplasm
    • Clinical hemolysis may occur with low titers (1:64), but usually the titers are ≥1:1000
  • Complement assessments (C3, C4, CH50)
  • Quantification of IgG, IgA and IgM
• Once hemolysis is diagnosed, establish any associated secondary diagnosis

Differential Diagnosis

• Hemoglobinopathies
• Paroxysmal cold hemoglobinuria
• Paroxysmal nocturnal hemoglobinuria – PNH
• Thalassemias
• Connective tissue disease
• Antiphospholipid syndrome – APS

Pharmacogenetics and Therapeutic Drug Monitoring

Screening

Monitoring

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

General References