The cold agglutinin syndrome is a form of autoimmune hemolytic anemia due to cold reacting antibodies and is classified as primary (idiopathic) or secondary.

Primary cold agglutinin disease

Usually associated with monoclonal cold-reacting autoantibodies. Occurs after the fifth decade of life, with a peak incidence at approximately age 70 years.

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 and is caused by infection.

Epidemiology

• Incidence – 1/100,000 in U.S.
• Primary cold agglutinin disease is observed in older patients, usually in patients older than 50 years, with a peak incidence at age 70
• Secondary cold agglutinin disease associated with infections is the type most commonly observed in children and young adults
• Sex – In general, no predilection exists for either sex, although some report a female predilection in older populations

Risk Factors

• Presence of lymphoproliferative disorders
• Infectious process
  • Mycoplasma pneumonia
  • Influenza A and B
  • Adenoviral infection
  • Mononucleosis
  • Malaria
• Genetic
  • Mutations – Trisomy 3 and 12
• Autoimmune disorders (SLE, systemic sclerosis)

Pathophysiology

• Termed cold agglutinin because they cause human red blood cell to agglutinate at 4ēC
• Cold-reacting autoantibodies are usually IgM, occasionally IgG, and rarely IgA.
• May be polyclonal, with the presence of kappa and gamma light chains, or
• Monoclonal, with a single type of light chain, most commonly,
• Immunoglobulin-mediated deposition of complement on red cell membranes

Clinical Presentation

• Hemolytic anemia is often the sole manifestation
• Acrocyanosis, Raynaud phenomenon, livedo reticularis
• Chronic cold agglutinin disease rarely exists

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
  • DAT specific for C3d and IgG
  • Serum cold agglutinin testing
    • Low levels may also be found in healthy adults, peripheral vascular disease, nonlymphoid neoplasm
    • Clinical hemolysis may occur with low titers (1:64), but usually the titers are greater than or equal to 1:1000
  • Complement assessments (C3, C4, CH50)
  • Quantification of IgG, IgA and IgM

Differential Diagnosis

• Hemoglobinopathies
• Paroxysmal cold hemoglobinuria
• Paroxysmal nocturnal hemoglobinuria (PNH)
• Thalassemias