Cold Agglutinins


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Subject: Cold Agglutinins

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  • Autoantibodies with specificity against RBC determinants that react at low temperature but not at body temperature. (Reactions against i determinants are less common.) The cold-reactive agglutinins are of the IgM class immunoglobulins; very rarely IgG. The IgM autoantibodies bind at low temperature to complement on the RBC membrane.

  • Normal titer: <1:32 (negative result).


  • Hemolytic anemia, particularly in the presence of lymphoproliferative disorders

  • When the clinical symptomatology suggests cold agglutinin disease


  • Cold agglutinin titers above 1:32 are diagnostic for the presence of cold agglutinin disease. The titer in affected patients may be >1,000.


  • Blood must be collected, clotted, and the serum separated at 37°C, and in addition, the sample must be maintained at 37°C. Alternatively, it can be collected on EDTA at room temperature, but then, it must be warmed for at least 15 minutes at 37°C.

  • The direct (Coombs) antiglobulin test is positive against C3d and C4d components of complement.

  • Low levels may also found in healthy individuals and those with peripheral vascular disease or nonlymphoid neoplasm.

  • Cold-reacting autoantibodies are mostly IgM, occasionally IgG, and rarely IgA. May be polyclonal, also can be monoclonal usually with kappa light chain.

  • Refrigeration of blood at any time adversely affects the results, as does severely hemolyzed or lipemic specimens.