NDT Advance Access originally published online on March 2, 2007
Nephrology Dialysis Transplantation 2007 22(5):1465-1467; doi:10.1093/ndt/gfm073
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Pure red cell aplasia followed by disseminated intravascular coagulation in a haemodialysis patient receiving erythropoietin-ß
1Division of Nephrology and Dialysis, Desenzano del Garda Hospital and 2Department of Clinical Medicine, Nephrology and Health Science, University of Parma, Parma, Italy
Correspondence and offprint requests to: Dr Lucio Manenti, Divisione di Nefrologia e Dialisi, Azienda Ospedaliera Desenzano del Garda, Via Montecroce 14, 25015 Desenzano d/G (BS), Italy. Email: lucio.manenti{at}aod.it
Keywords: anti-erythropoietin antibodies; disseminated intravascular coagulation; erythropoietin-ß; haemodialysis; pure red cell aplasia; rheumatoid arthritis
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Introduction |
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Pure red cell aplasia (PRCA) is a rare disorder that leads to severe anaemia with selective erythroblastopenia. PRCA may be secondary to drugs or infections with viruses such as parvovirus B19, which is known to cause the depletion of red blood cell precursors; in other cases, it is associated with thymoma, B– or T–cell lymphoproliferative disorders and other malignancies. In addition, PRCA is sometimes associated with autoimmune diseases (e.g. systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) [1].
Although PRCA is very rare, the number of reported cases has dramatically increased in recent years, predominantly in patients with chronic kidney disease (CKD)–associated anaemia receiving subcutaneous injections of recombinant epoetin (rEpo) [1,2]. In this setting, PRCA is clearly associated with anti-erythropoietin antibodies (AEA), which have frequently been detected in the sera of affected patients and have been shown to be involved in the pathogenesis of the disease.
AEA have also been studied in patients with PRCA associated with autoimmune diseases, such as SLE, RA and Sjögren's syndrome; some studies have shown that they test positive in a significant proportion of SLE patients [3]; however, these results have not been confirmed by other authors [4]. Therefore, the prevalence of AEA in autoimmune conditions is still unclear and their potential pathogenetic role needs to be elucidated.
We describe here a case of PRCA associated with rEpo-ß administration in a haemodialysed patient with a history of RA, who also manifested a clinical picture of disseminated intravascular coagulation (DIC).
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Case report |
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A 79-year-old man with end-stage renal disease of unknown origin started haemodialysis in January 2004. About 10 years earlier, the patient had been diagnosed with seropositive RA without extra-articular manifestations, and was given treatment with hydroxychloroquine sulphate, which he was still taking at the time he began haemodialysis. In March 2004, because of CKD-associated anaemia (Hb level 10 g/dl), he started subcutaneous rEpo-ß therapy (4000 IU, three times per week). Two months later the dose was lowered to 4000 IU/week, since haemoglobin level reached 12 g/dl. Eleven weeks later, the patient's haemoglobin dropped (8.5 g/dl) and the dose of epoetin-ß was increased back to the initial dosage, obtaining a good clinical response.
Three months later, haemoglobin level decreased again and the rEpo-ß dose was raised to 5000 IU three times per week, but without a clinical response. In March 2005, the patient received his first blood transfusion and in May 2005, although rEpo-ß was given at a dose of 10 000 IU three times per week, haemoglobin level further decreased (6.7 g/dl) and blood transfusions were repeated. Total iron, total iron binding capacity, ferritin, lactate dehydrogenase, aptoglobin, prothrombin time and activated partial thromboplastin time were normal. Folic acid and vitamin B12 deficiencies were ruled out. Gastroscopy and colonoscopy were performed because of positive occult blood in the stool, but bleeding lesions were ruled out. No reticulocytes were detectable on a blood smear and a progressive lowering of platelet count was found (from 91 000/mm3 to 37 000/mm3). Serological investigations for Parvovirus B19 infection were negative. A bone marrow aspirate revealed selective depletion of erythroblast precursors with normal granulopoiesis and megakaryopoiesis. PRCA was suspected and rEpo-ß was stopped. AEA tests were performed in two independent laboratories, using different methods (double antigen sandwich ELISA and radioimmunoprecipitation assay (RIPA)) and were both found to be highly positive (respectively 96 053 ng/ml, normal <10 ng/ml; and 350 UI/ml, normal if negative). Prednisone (1 mg/kg/day, orally) was thus started (Figure 1). Unfortunately, haemoglobin was persistently low and the rate of blood transfusion was three units every two weeks.
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Two months later, the patient presented with severe bleeding from the cutaneous insertion of the haemodialysis needle and diffuse subcutaneous haematomas. Disseminated intravascular coagulation (DIC) was diagnosed on the basis of prolonged activated partial thromboplastin (45 seconds; normal range 26–38) and prothrombin (international normalized ratio, INR, 1.6) times, together with elevated D-dimer levels (>1005, normal range 50–192), persistently low platelet count (26 000/mm3) and very low fibrinogen levels (<50 mg/dl, normal 150–450). According to the DIC scoring system (which differentiates between overt and non overt DIC) a diagnosis of overt DIC could be made. The patient started plasma therapy and continued blood transfusions; besides autoimmune diseases, all the potential causes of DIC (i.e. sepsis, neoplasms) were excluded. The patient continued plasma, blood and occasional platelet transfusions without clinical improvement; an attempt to start low-weight heparin to control DIC determined the reappearance of haematomas. He continued prednisone without clinical response. In September 2005, a second AEA test using ELISA technique was performed and was found to be still positive, although at a lower level (2330 ng/ml). In October 2005, the patient died because of cardiovascular complications.
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Discussion |
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PRCA caused by AEA has been recognized as a rare but severe side-effect of treatment with rEpo. In Europe, where most cases have occurred, AEA-associated PRCA was reported in 183 patients receiving subcutaneous rEpo-
(Eprex®) alone and in only 8 patients treated with rEpo-ß (NeoRecormon®) alone [1].
Notably, this is the first report of recombinant Epo-induced PRCA occurring in a patient with RA. Some peculiarities of our case, such as the strikingly high level of circulating AEA (the highest reported level being 30 000 ng/ml) [4] and the occurrence of PRCA during rEpo-ß treatment (which is very rare as compared with rEpo-) [1], suggest that an aberrant immune reactivity to recombinant proteins such as rEpo may have occurred in our patient; it is likely that the presence of an autoimmune disease such as RA may have favoured the development of PRCA. This notion is reinforced by the finding of AEA in some cases of autoimmune disease-associated PRCA [3,5–6].
Moreover, our patient developed DIC soon after PRCA. A consumption coagulopathy, although rarely, has been described in patients with active connective tissue diseases (e.g. juvenile rheumatoid arthritis) [7]. The close temporal relationship between PRCA and DIC in our patient strongly suggested a correlation between the two clinical pictures. Moreover, a systematic analysis of PRCA cases [1] reveals that as soon as patients develop rEpo-induced PRCA, they also experience a significant drop in platelet count; this was interpreted as a direct effect of rEpo on megakaryopoiesis (which appeared to be normal on a bone marrow aspirate in our patient), or as a more complex interaction between platelet formation and erythroid precursor cells, but it cannot be excluded that it represents the manifestation of occult DIC. Previously reported cases never describe fibrinogen or D-dimer values to rule out an initial coagulopathy in cases of thrombocytopenia following PRCA [1].
Several factors contribute to the pathogenesis of DIC, including abnormal activation of the coagulation cascade with increased generation of thrombin (which is usually thought to result from enhanced expression of tissue factor by endothelial and mononuclear cells), suppression of physiological anticoagulation mechanisms, and impaired fibrinolysis [8]. In our case, it can be speculated that the pathophysiological link between PRCA and DIC lies in the coagulation triggering by circulating immune complexes consisting of AEA; immune complexes may interact with endothelial and mononuclear cells, inducing their activation [8]. AEA levels were indeed exceptionally high in our patient, and we subcutaneously administered high doses of rEpo for three consecutive months, perhaps reaching a critical mass of circulating immunocomplexes. In addition, the history of RA, a disease hallmarked by the presence of circulating immune complexes, might have predisposed our patient to develop such a complication. Finally, it can also be postulated that AEA induced endothelial or mononuclear cells to release pro-inflammatory cytokines, which have been shown to impair physiological anticoagulation and fibrinolytic mechanisms in vivo [8].
Recent studies have shown that immunosuppressive therapy hastens the disappearance of circulating AEA, and allows endogenous erythropoiesis to recover to pre-treatment levels [9]. In a retrospective study, 78% of the patients who received immunosuppressive therapy recovered; no patients recovered without immunosuppression [9]. The immunosuppressants used were generally corticosteroids, cyclophosphamide or cyclosporine [10]. One case successfully recovered after rituximab therapy [11]. In our case, we used corticosteroids alone and waited for a stabilization of DIC before trying a more aggressive immunosuppressive regimen, but the patient rapidly worsened and died. Steroids determined a significant reduction in the AEA level, but no apparent clinical benefit was obtained and the reticulocyte count was repeatedly zero.
In conclusion, our case suggests a possible disease continuum between RA and rEpo-induced PRCA. Attention must be paid to the fact that our patient subsequently developed PRCA and DIC, which can be an occult but possibly underestimated complication of rEpo-induced PRCA; we propose to screen activated partial thromboplastin and prothrombin times, D-dimer and fibrinogen levels in PRCA patients, especially in the presence of thrombocytopenia.
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Acknowledgement |
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The authors gratefully acknowledge Prof. C. Buzio for his insightful review of the manuscript.
Conflict of interest statement. None declared.
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References |
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Accepted in revised form: 23. 1.07
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