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Answer: Many patients have antibodies in their plasma which bind to antigens present on the surface of their own red blood cells. Commonly, these autoantibodies are easily detectable in the laboratory at cold temperatures (4° C) but may be very weak or undetectable when the samples are warmed to body temperature (37° C). While cold autoantibodies are generally not clinically significant and do not cause hemolysis in the patient, they may delay serologic testing of the blood. Autoantibodies can obscure the identification of underlying clinically significant alloantibodies, requiring additional testing to find appropriate crossmatch compatible units for transfusion. Although the majority of cold autoantibodies are benign, they may rarely be associated with hemolysis. Cold agglutinin disease (CAD) is a rare type of autoimmune hemolytic anemia caused by cold autoantibodies. The autoantibodies found in CAD differ from the commonly encountered cold autoantibodies. They are often present at an extremely high titer (≥ 1:1000 at 4° C) and also demonstrate a high thermal amplitude, making them easily detectable at temperatures above 30° C. Blood samples in the laboratory may spontaneously agglutinate, and the peripheral smear shows clumps of agglutinated red blood cells (Figure 1).