Development Of Pure Red Cell Aplasia Research Articles

Positive response of a hemodialysis patient with pure red cell aplasia on recombinant human erythropoietin therapy to cyclosporine and Roxadustat.

Recombinant human erythropoietin (rHuEPO) is commonly used to treat anemia associated with chronic kidney disease (CKD). EPO-induced Pure Red Cell Aplasia (PRCA) is a rare condition of profound anemia with EPO treatment. Upon finding the development of EPO-induced PRCA, the treatment requires immediate withdrawal of EPO therapy and initiate new treatments with immunosuppression or renal transplantation. Anti-EPO antibody assay is not always positive in EPO-induced PRCA. Here, we report a case on the sudden development of PRCA in a hemodialysis patient receiving EPO and how we treated the condition successfully with cyclosporine and subsequently maintained the hemoglobin with Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). Even though the anti-EPO antibody was negative by Enzyme Linked Immunosorbent Assay (ELISA) in our case, the clinical course, the markedly reduced reticulocyte count < 10,000/μL, the bone marrow (BM) biopsy revealing reduced erythroblasts, and its subsequent response to cyclosporine, were similar to EPO-induced PRCA. The clinical picture of EPO-induced PRCA, the limitation of the EPO-neutralizing antibody (Ab) assay, and treatment strategies were discussed.

Prevalence of Pure Red Cell Aplasia Following Major ABO-Incompatible Hematopoietic Stem Cell Transplantation.

BackgroundPure red cell aplasia (PRCA) is one of the important complications in major ABO-incompatible allogeneic hematopoietic stem cell transplantation (HSCT). The established pathogenic factor of PRCA is the persistence of high anti-donor isohemagglutinins. As previously verified, the conditioning regimen and donor type were the factors associated with the development of PRCA in the small-sized studies. Currently, the prevalence, risk factors, and prognosis of PRCA are still worth studying to provide evidence.MethodsWe conducted a prospective nested case-control study to determine the prevalence, donor-related factors, and the outcomes of PRCA following major ABO-incompatible transplantation. A total of 469 patients who underwent ABO-incompatible grafts were observed.ResultsNone of the patients were diagnosed with PRCA with minor or bidirectional ABO-incompatible HSCT. Thirteen of the187 patients (7%; 95% confidence interval [CI], 3.9%–11.9%) developed PRCA following major ABO-incompatible HSCT. Eleven of the 13 patients with PRCA recovered entirely. Donor type was an independent factor associated with post-HSCT PRCA (odds ratio [OR]=0.030; 95% CI, 0.003–0.321; P=0.004). The cumulative incidence rates of post-HSCT PRCA in the context of major ABO-incompatible HSCT were 0.8%, 13.1%, and 27.2% for the haploidentical donor (HID), unrelated donor, and matched related donor, respectively. No significant influence of PRCA on transplantation outcomes was observed.In conclusion, post-HSCT PRCA is a rare and less threatening complication in major ABO-incompatible HSCT. The majority of patients with PRCA could recover. Additionally, HIDs for recipients may have a low risk of post-HSCT PRCA. This trial was registered at www.chictr.org.cn (#ChiCTR2000041412).

Resolution of epoetin-induced pure red cell aplasia 2 years later, successful re-challenge with continuous erythropoiesis receptor stimulator

Epoetin-induced pure red cell aplasia (PRCA) is most commonly associated with epoetin-a; nevertheless, its occurrence has been reported in epoetin-β and darbepoetin-a. We report a young hemodialysis patient who developed PRCA 2 years after receiving intravenous epoetin-β. Epoetin- induced PRCA was confirmed by bone marrow aspiration, associated with markedly elevated anti-erythropoietin antibody. He was treated with prednisolone and cyclophosphamide for 3 months but continued to be transfusion-dependent. 17 months after the development of PRCA, he was started on intravenous continuous erythropoiesis receptor stimulator (CERA) in view of frequent transfusions. He tolerated the CERA injection well and the hemoglobin level stabilized 7 months later. Repeat bone marrow aspiration confirmed complete resolution of PRCA with disappearance of anti-erythropoietin antibody. To date, he maintained a stable hemoglobin level and has been transfusion-independent for the past 1 year. This is the first in the literature that reported the utilization of CERA in epoetin-induced PRCA. Very low or undetectable level of anti-erythropoietin antibody might be the key to the success of re-challenge strategy in cases of epoetininduced PRCA. Thus, routine checking of anti-erythropoietin antibody before the rechallenge with an alternative erythropoietin product is highly recommended.

Characteristic Changes in Anti-erythropoietin Antibodies in a Peritoneal Dialysis Patient Who Developed Pure Red Cell Aplasia

Although cases of anti-erythropoietin (anti-EPO) antibody-induced pure red cell aplasia (PRCA) have been reported since 1998, the role of anti-EPO antibodies in the development of PRCA is controversial, with many conflicting opinions. Here, we present a patient who had serial serum anti-EPO antibody levels measured both before and after the development of PRCA to observe the relationship between serial changes in anti-EPO antibody and hemoglobin levels. Enzyme-linked immunosorbent assays were used for the detection of anti-EPO antibodies. The patient's serum anti-EPO antibody levels showed a characteristic change over time: negative before the development of PRCA, strongly positive when PRCA was diagnosed, decreasing after receiving prednisone, and eventually became negative. More importantly, an inversely close association between changes in serum anti-EPO antibody and hemoglobin levels was shown. The characteristic changes in this case indicate that anti-EPO antibody might have a role in the development of PRCA, and monitoring the titer of anti-EPO antibody may be of great value in the diagnosis and treatment of PRCA.

A case of systemic lupus erythematosus complicated by pure red cell aplasia and idiopathic portal hypertension after thymectomy

We describe a 49-year-old woman who presented in 2002 with pure red cell aplasia (PRCA), systemic lupus erythematosus (SLE), and idiopathic portal hypertension (IPH) that developed following a thymectomy. She underwent a thymectomy at 40 years of age to treat myasthenia gravis. PRCA developed 3 years after the thymectomy and she was successfully treated with cyclosporin. Systemic lupus erythematosus and IPH were diagnosed 6 years later. We conclude that immunological dysfunction resulting from the thymectomy contributed significantly to the subsequent development of PRCA, SLE, and IPH in this patient. This is the first report to describe this extremely rare occurrence.

Antibody-mediated pure red cell aplasia (PRCA): epidemiology, immunogenicity and risks

Although epoetin-induced antibody (Ab)-mediated pure red cell aplasia (PRCA) was very rare prior to 1998, a large increase in the number of global cases was observed from 1999 to 2002 in patients treated with erythropoiesis-stimulating agents (ESAs) for the anaemia associated with chronic kidney disease (CKD). The number of global cases of this immunological form of PRCA has declined precipitously since 2003 following increased awareness of this disorder and changes in the handling and administration of the formulation of epoetin-alpha (EPO) that was associated with the majority of cases. Current recommendations state that patients should stop treatment immediately following a diagnosis of Ab-mediated PRCA and not resume treatment with the same or another ESA. The feasibility of re-treatment following remission from PRCA or during ongoing immunosuppressive therapy is currently under investigation. The immunological mechanism for developing Ab-mediated PRCA is unknown, but a variety of factors may increase the immunogenicity of epoetin or other ESAs. Product-related factors that have the potential to impact on immunogenicity include sequence variations in proteins, the degree and nature of protein glycosylation, the manufacturing process, handling and storage, and components and properties of the product formulation. Patient-related factors associated with developing Ab-mediated PRCA include skin reactions, immune status and treatment history. Increased awareness among physicians of the factors contributing to the development of PRCA and its distinguishing clinical features has coincided with studies aimed at identifying effective therapies for this disorder. A number of immunosuppressive therapies have been shown recently to reconstitute effectively the erythropoietic response in patients with PRCA. However, therapeutic approaches for this serious immunological reaction to recombinant ESAs remain investigative.

Effect of switching from subcutaneous to intravenous administration of epoetin-α in haemodialysis patients: Results from a Swedish multicentre survey

In 2002, many haemodialysis patients were switched from subcutaneous (s.c.) to intravenous (i.v.) administration of epoetin-alpha following reports of antibody formation and development of pure red-cell aplasia in patients treated via the s.c. route. We evaluated the possible effect of this change in the route of administration on haemoglobin (Hb) levels and epoetin-alpha requirements. This retrospective survey involved 223 haemodialysis patients from 25 Swedish centres. Variables were recorded before and after a mean period of 213 days (range 89-297 days) after the change in the route of administration. The mean epoetin-alpha do had to be increased from 159+/-104 to 185+/-122 U/kg/week (p<0.0001) to maintain a constant Hb level (121+/-12 vs 120+/-11 g/l). Plasma ferritin, albumin, C-reactive protein, iron, iron transferrin saturation and body mass index remained constant. The relative increase in epoetin-alpha dose was negatively correlated with the s.c. dose prior to the switch (R=-0.3; p<0.0001), with the most pronounced dose increases occurring in patients who received a low s.c. dose. A switch from s.c. to i.v. administration of epoetin-alpha in haemodialysis patients was accompanied by an increase in the mean dose requirement of 15%. This increase may be less pronounced in patients receiving high s.c. doses prior to the switch.

Pure red cell aplasia associated with expansion of CD3+ CD8+ granular lymphocytes expressing cytotoxicity against HLA-E+ cells.

T-cell granular lymphocyte-proliferative disorder (T-GLPD) is characterized by the proliferation of cytotoxic T lymphocytes, and is often associated with pure red cell aplasia (PRCA). The mechanism involved in the development of PRCA in T-GLPD is unknown. Peripheral blood mononuclear cells were isolated from 20 patients with T-GLPD. Ten patients had associated PRCA. Granular lymphocytes (GLs) of T-GLPD are positive for CD94, but not NKG2A. To clarify the functional role of CD94 in T-GLPD, we performed a cytotoxicity assay against the trophoblast cell line, BeWo, which is known to express human leucocyte antigen (HLA)-E, a natural ligand of CD94, and is deficient in other HLA class I and class II antigens. GLs isolated from T-GLPD with PRCA patients killed BeWo cells more significantly than GLs from T-GLPD without PRCA patients. Furthermore, GLs from T-GLPD with PRCA were significantly stimulated by a monoclonal antibody against CD94, whereas those of T-GLPD without PRCA were not. Taken together, HLA-E, a ligand of CD94, was suggested to stimulate CD94+ cells to kill HLA-E+ cells in T-GLPD with PRCA. GLs of T-GLPD with PRCA have a potential positive activity against HLA-E+ cells, whereas GLs from T-GLPD without PRCA do not. CD94 may play a key role in the pathogenesis of PRCA in T-GLPD.

Initial predictors of development of pure red cell aplasia in myasthenia gravis after thymectomy

Pure red cell aplasia (PRCA) is well known to be concomitant with myasthenia gravis (MG), but it is difficult to predict the development of PRCA in patients with MG. Of 135 patients with MG, four (2.9%) had PRCA. All patients developed PRCA after thymectomy during a period when MG was in remission. The frequencies of thymoma, bulbar involvement and high anti-acetylcholine receptor (AChR) antibody levels were significantly higher in four patients with PRCA. Japanese MG patients with these characteristics at presentation were at significant risk for the development of PRCA after thymectomy.

Successful Treatment of Pure Red Cell Aplasia with Plasmapheresis in a Patient with Systemic Lupus Erythematosus

Pure red cell aplasia (PRCA) is a rare cause of anemia associated with systemic lupus erythematosus (SLE), and fewer than 20 cases have been reported. The development of PRCA may be mediated by an autoimmune mechanism which is supported by the presence of antibodies that impair various stages and mechanisms of erythropoiesis, by the association with immunological disorders or lymphoma, and by a favorable response to immunosuppressive drugs, antilymphocyte globulin, thymectomy, and splenectomy. However, these therapies have not been successful in all patients with PRCA. We report our experience with a 31-year-old female patient with SLE who developed PRCA that did not respond to immunosuppressive therapies. However, complete normalization of erythropoiesis was achieved after the removal of the autoantibodies by plasmapheresis, and the patient has now maintained a normal hemoglobin level for more than eight months. We suggest that plasmapheresis might be tried in the treatment of PRCA cases before other more aggressive therapies are commenced.

Anti-A isoagglutinin as a risk factor for the development of pure red cell aplasia after major ABO-incompatible allogeneic bone marrow transplantation.

Delayed erythropoiesis and pure red cell aplasia (PRCA) have been reported after major ABO-incompatible BMT. We attempted to find risk factors for the development of PRCA in 27 patients who underwent major ABO-incompatible BMT. In all patients, the donor marrow was depleted of RBCs before infusion. In 22 patients, isoagglutinins were determined until they disappeared. In eight (29.6%) out of 27 patients, bone marrow examination following BMT showed the findings of PRCA. We analyzed various clinico-pathologic risk factors and isoagglutinin type was the only significant risk factor. Patients with anti-A isoagglutinins against donor RBC developed PRCA more frequently than patients with anti-B (8/17 vs 0/9). Median days to the disappearance of isoagglutinins tended to be longer in patients with PRCA (PRCA vsnon-PRCA, 200 vs 66 days) and in cases with anti-A isoagglutinins (anti-A vsanti-B, 160 vs 51 days). Times to disappearance of isoagglutinins correlated with times to reticulocytes over 1% and initial appearance of donor type RBC (R2 = 0.708 and 0.711). In conclusion, RBC engraftment following major ABO-incompatible BMT was dependent on the disappearance of isoagglutinins against donor RBC, and anti-A isoagglutinin was a risk factor for the development of PRCA after major ABO-incompatible allogeneic BMT. Bone Marrow Transplantation (2000) 25, 179-184.

Pure red cell aplasia associated with B cell lymphoma: Demonstration of bone marrow colony inhibition by serum immunoglobulin

A 58-year old male with follicular small cleaved B cell lymphoma developed pure red cell aplasia (PRCA) during chemotherapy. To understand the etiology of the PRCA, we studied the effects of patient sera on the progenitor cell colony formation of normal human bone marrow cells in vitro. We demonstrated a marked inhibition of normal bone marrow progenitor cell colony formation by patient sera, but not pooled normal human sera. Immunoglobulin was then precipitated from patient sera for similar studies. The majority of the precipitated immunoglobulin was of the IgG type. The immunoglobulin fraction markedly inhibited normal bone marrow progenitor cell colony formation, whereas the non-immunoglobulin fraction was not inhibitory. The presence of inhibitory serum immunoglobulin correlated with the hematologic status of the patient. We conclude that the development of PRCA in patients with B cell lymphoma may be due to a serum IgG inhibitor of bone marrow progenitor cell growth.