Diagnostic Considerations

Conditions to consider in the differential diagnosis of cold agglutinin disease include the following:

Cryoglobulinemia
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

Cryoglobulinemia

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).

Warm antibody–mediated autoimmune hemolytic anemia

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]}

Episodic hemoglobinuria following cold exposure

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.^[27]March hemoglobinuria (episodic) is clearly related to exertion.

Neoplasms

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.^[47]

Drug-induced immune hemolytic anemia

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.

Differential Diagnoses

Workup

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Media Gallery

Peripheral blood smear showing several clumps of RBCs with the largest in the center. These are typical of aggregates seen in persons with cold agglutinin disease.
Blood smear showing spherocytic and agglutinated red blood cells.

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Author

Salman Abdullah Aljubran, MD Allergist and Immunologist, Associate Director of FARE Center of Excellence, Children's Mercy Hospitals and Clinics; Assistant Professor of Medicine and Pediatrics, Division of Allergy, Asthma and Immunology, University of Missouri-Kansas City School of Medicine

Salman Abdullah Aljubran, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American Medical Association, Clinical Immunology Society

Disclosure: Nothing to disclose.

Coauthor(s)

Richard F Lockey, MD University Distinguished Health Professor, Professor of Medicine, Pediatrics and Public Health, Joy McCann Culverhouse Chair in Allergy and Immunology, University of South Florida College of Medicine; Director, Division of Allergy and Immunology, James A Haley Veterans’ Hospital

Richard F Lockey, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, American Association for the Advancement of Science, American College of Occupational and Environmental Medicine, American College of Chest Physicians, American College of Physicians, American Medical Association, Florida Medical Association

Disclosure: Nothing to disclose.

Chief Editor

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Nicolas A Camilo, MD Consulting Staff, Mountain States Tumor Institute, Division of Pediatric Hematology-Oncology, St Luke's Regional Medical Center