Correspondence

Pure Red-Cell Aplasia Secondary to Antierythropoietin Antibodies

N Engl J Med 2003; 349:2572-2573December 25, 2003

Article

To the Editor:

The use of recombinant human erythropoietin in patients with kidney disease is widespread and has been associated with few complications. Recent reports have suggested that the incidence of pure red-cell aplasia is increasing among European patients, who are often treated with subcutaneous epoetin alfa (Eprex).1,2 Neutralizing antierythropoietin antibodies were detected in these patients. We describe a case of pure red-cell aplasia in an American patient who was receiving epoetin alfa (Procrit, Ortho Biotech). Antierythropoietin antibodies were found to be neutralizing in vivo and in a murine erythroid cell line.

A 66-year-old woman with polycystic disease had chronic renal failure and anemia. In August 2002, when her hematocrit was 33.3 percent, subcutaneous administration of 5000 units of epoetin alfa was initiated. The patient was hospitalized in April 2003 because of a hematocrit of 15.8 percent. Gastrointestinal evaluations revealed no abnormalities. Blood was transfused, but the patient was hospitalized again in May with a hematocrit of 17.5 percent, a mean corpuscular volume of 86 μm³, and normal white-cell and platelet counts. The reticulocyte count was 0. Examination of a peripheral-blood smear revealed normocytic, normochromic red cells. Immunoassays for erythropoietin showed undetectable levels of hormone, suggesting the presence of neutralizing antierythropoietin antibodies. Examination of a bone marrow biopsy specimen revealed a myeloid-to-erythroid ratio of 210 to 1. Myeloid maturation was normal. Megakaryocytes were present. Rare erythroblasts were seen. The results of flow-cytometric and cytogenetic studies were normal. Testing for neutralizing antibody was performed by Amgen with the use of an immunoassay (BIAcore) and a bioassay involving a murine cell line requiring erythropoietic agents for growth.

Anti–epoetin alfa antibodies were detected at a concentration of 10.18 μg per milliliter with IgG1, IgG2, and IgG4 isotypes. The bioassay detected neutralizing antibodies, as indicated by the specific absence of cell growth in the presence of the patient's serum. The administration of epoetin alfa was discontinued. The patient has since remained transfusion-dependent, with undetectable serum levels of erythropoietin for several months.

Recombinant human erythropoietin differs in glycosylation from the native molecule. This difference may affect molecular conformation, exposing an antigenic protein moiety, with subsequent development of high-affinity antibodies that neutralize native erythropoietin and thus result in pure red-cell aplasia.

A French group reported the development of pure red-cell aplasia after erythropoietin therapy, and the initial speculation was that this rare complication might be due to selected lots of the hormone available on the European market.1,2 Our observations suggest that pure red-cell aplasia due to antierythropoietin antibodies may occur with a variety of recombinant preparations. Pure red-cell aplasia should be included in the differential diagnosis of refractory anemia in patients who are receiving recombinant human erythropoietin. Undetectable serum levels of erythropoietin by immunoassay should alert physicians to the possible presence of pure red-cell aplasia secondary to neutralizing antierythropoietin antibodies.

Steven S. Guest, M.D.
Santa Clara Valley Medical Center, San Jose, CA 95128
steve.guest@hhs.co.santa-clara.ca.us

Lee Levitt, M.D.
Stanford University School of Medicine, Stanford, CA 94305

2 References

1. 1

   Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002;346:469-475
   Full Text | Web of Science | Medline

2. 2

   Eckardt K, Casadevall N. Pure red-cell aplasia due to anti-erythropoietin antibodies. Nephrol Dial Transplant 2003;18:865-869
   CrossRef | Web of Science | Medline

Citing Articles (5)

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   Andreas Tiede, Roswith Eisert, Andreas Czwalinna, Wolfgang Miesbach, Inge Scharrer, Arnold Ganser. (2010) Acquired haemophilia caused by non-haemophilic factor VIII gene variants. Annals of Hematology 89:6, 607-612
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   Jordan M. Schecter, J. Gregory Mears, Bachir Alobeid, Paul J. Gaglio. (2007) Anti-erythropoietin antibody–mediated pure red cell aplasia in a living donor liver transplant recipient treated for hepatitis C virus. Liver Transplantation 13:11, 1589-1592
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   R. Todd Stravitz, Harold Chung, Richard K. Sterling, Velimir A. Luketic, Arun J. Sanyal, Angie S. Price, Amy Purrington, Mitchell L. Shiffman. (2005) Antibody-Mediated Pure Red Cell Aplasia Due to Epoetin Alfa During Antiviral Therapy of Chronic Hepatitis C. The American Journal of Gastroenterology 100:6, 1415-1419
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   Heiner Frost. (2005) Antibody-mediated side effects of recombinant proteins. Toxicology 209:2, 155-160
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   L. Nigg, U. Schanz, P. M. Ambuhl, J. Fehr, E. B. Bachli. (2004) Prolonged course of pure red cell aplasia after erythropoietin therapy. European Journal of Haematology 73:5, 376-379
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