Pure red cell aplasia

Kharagjitsingh, A.V. et al., Incidence of recombinant erythropoietin (EPO) hyporesponse, EPO-associated antibodies, and pure red cell aplasia in dialysis patients, Kidney Int., 68, 1215, 2005. 

Pure red cell aplasia (PRCA) PRCA has been reported in a limited number of patients exposed to epoetin alfa. This has been reported predominantly in patients with CRF. Evaluate any patient with loss of response to epoetin alfa for the etiology of loss of effect. Discontinue epoetin alfa in any patient with evidence of PRCA and evaluate the patient for the presence of binding and neutralizing antibodies to epoetin alfa, native erythropoietin, and any other recombinant erythropoietin administered to the patient. In patients with PRCA secondary to neutralizing antibodies to erythropoietin, do not administer epoetin alfa, and do not switch such patients to another product as anti-erythropoietin antibodies cross-react with other erythropoietins. 

An inverse log-linear relationship has been found between hematocrit and plasma erythropoietin in anemic patients with normal renal function. Patients with chronic renal failure have inappropriately low erythropoietin levels for their degree of anemia [10]. The severity of anemia correlates with the extent of renal dysfunction. Intravenous or subcutaneous recombinant human erythropoietin given three times a week is the treatment of choice. Some patients seem to do well on only one injection per week. One version of erythropoietin, Epocrit, marketed outside the United States, has been associated with pure red cell aplasia. 

Allergic reactions to ESAs have been infrequent. There have been a small number of cases of pure red cell aplasia (PRCA) accompanied by neutralizing antibodies to erythropoietin. PRCA was most commonly seen in dialysis patients treated subcutaneously for a long period with a particular form of epoetin alfa (Eprex with a polysorbate 80 stabilizer rather than human serum albumin) that is not available in the USA. After regulatory agencies required that Eprex be administered intravenously rather than subcutaneously, the rate of ESA-associated PRCA diminished. However, rare cases have still been seen with all ESAs administered subcutaneously for long periods to patients with chronic kidney disease. 

Epoetin alfa Agonist of erythropoietin receptors expressed by red cell progenitors Stimulates erythroid proliferation and differentiation, and induces the release of reticulocytes from the bone marrow Treatment of anemia, especially anemia associated with chronic renal failure, HIV infection, cancer, and prematurity prevention of the need for transfusion in patients undergoing certain types of elective surgery IV or SC administration 1-3 times per week Toxicity Hypertension, thrombotic complications, and, very rarely, pure red cell aplasia to reduce the risk of serious CV events, hemoglobin levels should be maintained < 12 g/dL... 

McKoy JM et al Epoetin-associated pure red cell aplasia Past, present, and future considerations. Transfusion 2008 48 1754. [PMID 18482185]... 

Anecdotal exposure to pentachlorophenol has been associated with aplastic anaemia and/or red-cell aplasia (Roberts, 1983). Thirteen cases of industrial, home and accidental pentachlorophenol exposure in 11 men and two women having aplastic anaemia, pure red cell aplasia and associated disorders were reported. Exposure levels were not known except for one patient, who had concentrations in the serum of 250 ng/mL and in bone marrow of 330 ng/mL (Roberts, 1990). 

Maeda H, Arai Y, Aoki Y, Okubo K, Okada T, Ueda Y. Leuprolide causes pure red cell aplasia. J Urol 1998 160(2) 501. 

Abbreviations EPO erythropoietin GH growth hormone PRCA pure red cell aplasia RIA radioimmunoassay SC subcutaneous TNF tumor necrosis factor. 

Boven K, Knight J, Bader F, Rossert J, Eckardt KU, Casadevall N Epoetin associated pure red cell aplasia in patients with chronic kidney disease solving the mystery. Nephrol. Dial. Transplant. (2005) 20 (Suppl 3) iii33-iii40. 

Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, Ugo V,Teyssandier I, Varet B, Mayeux P. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002 346 469-75. 

Gershon SK, Luksenburg H, Cote TR, Braun MM. Pure red-cell aplasia and recombinant erythropoietin. N Engl J Med 2002 346 1584-6. 

Ide, T., Sata, M., Nouno, R., Yamashita, F., Nakano, H., Tanikawa, K. Clinical evaluation of four cases of acute viral hepatitis complicated by pure red cell aplasia. Amer. X Gastroenterol. 1994 89 257-262... 

Creemers GJ, van Boven WP, Lowenberg B, van der Heul C. Azathioprine-associated pure red cell aplasia. J Intern Med 1993 233(l) 85-7. 

Pruijt JF, Haanen JB, Hollander AA, den Ottolander GJ. Azathioprine-induced pure red-cell aplasia. Nephrol Dial Transplant 1996 ll(7) 1371-3. 

Some 15 cases of thrombocytopenia, reversible after withdrawal of carbamazepine, have been published (SED-13, 147) (41,42). There have also been single case reports of reticulocytosis (SED-13,147) (43), leukopenia with thrombocytopenia with Henoch-Schonlein purpura (SEDA-18,63), hemolytic anemia, and pure red cell aplasia (SED-13,147) (44). 

Buitendag DJ. Pure red-cell aplasia associated with carbamazepine. A case report. S Afr Med J 1990 78(4) 214-15. 

Worldwide, 112 cases of pure red cell aplasia have been reported after subcutaneous administration of epoetin alfa (especially Eprex) in patients with chronic renal insufficiency. In these patients, neutralizing anti-eiythropoietin antibodies were detected (82-84) these antibodies cross-react with all other erythropoietin products. This adverse... 

In other reports from Canada and the UK, patients typically developed sudden worsening of anemia unresponsive to increasing doses of epoetin alfa or any other form of erythropoietin and became transfusion dependent (85). In patients who develop sudden lack of efficacy or worsening of anemia, typical causes of non-response (for example deficiencies of iron, folate, and vitamin B12, infection or inflammation, blood loss, hemolysis, and aluminium intoxication) should be investigated. If pure red cell aplasia is suspected and no cause can be identified, erythropoietin antibodies should be sought. 

The Australian Adverse Drug Reactions Advisory Committee has also received 12 reports of pure red cell aplasia associated with the use of epoetin alfa (Eprex) in patients with renal insufficiency (86). The patients were aged 28-76 years and the duration of epoetin alfa use, when known, was 4—13 months. 

Janssen-Ortho Inc, in association with Health Canada, have issued a Dear Health Professional letter about the addition of a boxed section to the product monograph of epoetin-alfa (Eprex). The addition recommends that epoetin alfa should be administered intravenously rather than subcutaneously in patients with chronic renal insufficiency. This advice is based on the fact that most of the worldwide reports of pure red cell aplasia in patients treated with epoetin alfa have been associated with subcutaneous administration. 

The suggested mechanism for these cases of pure red cell aplasia is an immune reaction that is probably induced by repeated, subcutaneous administration of a foreign protein, a biotechnologically processed erythropoietin. However, no antibodies toward darbepoetin alfa were detected in over 1534 patients treated for 2 years (87). 

A 70-year-old woman with a history of diabetes melhtus and renal insufficiency rapidly developed a severe anemia (with a hemoglobin concentration of 3.5 mmol/1). She had been treated with recombinant erythropoietin (4000 lU/ week) for 6 months with an initial favorable response (hemoglobin concentration between 6.8 and 7.5 mmol/1) (82). Her bone marrow showed pure red cell aplasia with early termination of maturation. The dose of recombinant erythropoietin was increased to 8000 lU/week. She required 3 units of packed red cells per month. 

Leikis MJ, Forbes IK, McMahon LP, Becker GJ. Resolution of pure red cell aplasia with continued production of low titer anti-epoetin antibodies. Chn Nephrol 2004 62(6) 481-2. 

Pure red cell aplasia has been reported in one bone marrow transplant recipient (11) and hemolysis has been observed in two other patients (5). 

Pure red cell aplasia occurred in a patient with cholestatic jaundice taking sodium aurothiomalate (SEDA-17, 275). Anemia has been reported occasionally with auranofin (0.1%) either as a direct effect or secondary to hematuria. 

Isolated anemia is not a common feature of the hemotoxic effects of interferon alfa, and pure red cell aplasia has been reported in two patients with chronic leukemia for several months (217,218). Both patients improved progressively after replacement of interferon alfa by hydroxyurea. However, one required erythrocyte transfusions for 14 months. 

The combination of interferon alfa with ribavirin is one of the most promising treatments for chronic hepatitis C. However, two patients developed rapid and particularly severe anemia within 4 and 6 weeks of combined treatment (415). One patient required erythrocyte transfusions, and both recovered after withdrawal. The combination of pure red cell aplasia due to interferon alfa and hemolytic anemia due to ribavirin was suggested to have accounted for this possible interaction. 

Hirri HM, Green PJ. Pure red cell aplasia in a patient with chronic granulocytic leukaemia treated with interferon-alpha. CUn Lab Haematol 2000 22(l) 53-4. 

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