Diagnostic ConsiderationsCryoglobulinemiaWarm antibody–mediated autoimmune hemolytic anemiaEpisodic hemoglobinuria following cold exposureNeoplasmsDrug-induced immune hemolytic anemia
Conditions to consider in the differential diagnosis of cold agglutinin disease include the following:
Warm antibody–mediated autoimmune hemolytic anemia (AIHA) - Some cases of cold agglutinin disease may be confused with this condition, particularly those in which the antibody has a high thermal amplitude
Episodic hemoglobinuria following cold exposure
Neoplasms - Especially of the lymphoid type
Drug-induced immune hemolytic anemia
Rheumatologic diseases manifesting Raynaud syndrome
Heparin-induced thrombocytopenia/thrombosis syndrome - Patients may have painful digits; anemia could be due to bleeding, but other manifestations are different
Systemic vasculitis, sometimes with hemolysis (systemic lupus and scleroderma)
Erythromelalgia in association with primary thrombocythemia and painful fingers and toes
Malaria and certain other infections
This condition has almost none of the features of cold agglutinin disease, except for a history of Raynaud syndrome and an elevated IgM level in some cases (but without hemolysis).
This must be differentiated from cold agglutinin disease, especially when no symptoms or findings suggest cold-induced acrocyanosis or Raynaud-type phenomenon. The cold agglutinin titer is a specific differentiating test, and a positive IgG-specific Coombs test result would exclude cold agglutinin disease. Examination of the peripheral blood smear is less specific, but finding typical RBC clumps would be unlikely in AIHA, unless it is a mixed IgG-IgM warm-cold autoimmune hemolytic anemia. [12, 15]
This can occur in more severe cases of cold agglutinin disease, so confusion may exist as to whether a patient has Donath-Landsteiner hemolytic anemia or cold agglutinin disease. The cold agglutinin titer is less than 1:64 in Donath-Landsteiner, and the result of the Donath-Landsteiner test for cold hemolysis is positive. (Donath-Landsteiner screening tests are warranted only if hemoglobinuria is detected in the patient.) The age of the patient is very important, as a diagnosis of Donath-Landsteiner hemolytic anemia is more probable in a child; in one study, the median age at presentation was 5 years and the peak incidence was in children 4 years and under.  March hemoglobinuria (episodic) is clearly related to exertion.
Neoplasms may be associated with a cold agglutinin or a cryoglobulin, giving rise to symptoms of Raynaud syndrome. If the cold agglutinin titer is elevated and a complement-specific Coombs test result is positive, the patient may have a neoplastic clone of lymphocytes producing the cold agglutinin disease. This would be important in terms of therapy and prognosis, because the underlying lymphoma may be responsive to treatment. Often, the more severe forms of cold agglutinin disease are associated with lymphoid malignancy. 
This condition may also be a source of confusion, particularly when the direct Coombs test result is positive only for complement. However, the specific drug used and low cold-agglutinin titer should help to distinguish drug-induced hemolytic anemia from cold agglutinin disease.
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