Key Takeaways

Cold agglutinin disease (CAD) is defined as an AIHA mediated by cold agglutinins (CAs),

CAD may be classified as primary and secondary

  • Primary
    • Also called idiopathic CAD or simply CAD.
    • No evidence of underlying disease such as aggressive lymphoma, other overt malignancies, or specific infections.
  • Secondary
    • Also called cold agglutinin syndrome
    • Complicating other specific diseases, such as Mycoplasma pneumoniae pneumonia, Epstein-Barr virus infection, or aggressive lymphoma

CAD accounts for about 15% of autoimmune hemolytic anemias (AIHA).

Cold agglutinins are autoantibodies (typically IgM) that are able to agglutinate red blood cells (RBCs) at an
optimum temperature of 3-4°C, but can also react at higher temperatures, depending on the thermal amplitude.

Most CAs in CAD have specificity for the I carbohydrate antigen, which is almost universally present at the RBC surface in adults and children older than age 18 months.

CAD is a distinct, clonal lymphoproliferative disease with monoclonal serum immunoglobulin present in majority of cases, typically immunoglobulin M-kappa (IgMk).

Clinical presentation typically includes combination of cold-induced symptoms, anemia, and hemolysis.

Febrile infections, major trauma, or major surgery can result in acute exacerbation of hemolytic anemia.

The diagnostic criteria for CAD include:

  • Chronic hemolysis
  • Positive polyspecific DAT
  • Positive monospecific DAT strongly positive for C3d
  • CA titer >64 at 4°C
  • No overt malignant disease by clinical (and, if required, radiological) examination

Treatment includes

  • Nonpharmacologic management
  • Clonally-directed therapies
    • Rituximab monotherapy
    • Rituximab and fludarabine combination therapy
    • Complement modulation?
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