Cold Agglutinin Disease

 

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