UMLS:C0002874 - FACTA Search

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Query: UMLS:C0002874 (aplastic anemia)
5,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophages (MAC) are important effector cells of the immune system but also play an essential role as regulatory cells in hematopoiesis. They originate from circulating monocytes (MO) as immature precursor cells that undergo terminal differentiation upon migration from the capillary bed into the various tissues. In the presence of serum, MAC maturation from blood MO is observed in vitro and can be followed by the expression of maturation-associated antigens (MAX.1, .3, .11, and .26; transferrin receptor, 13C2, CD16). We have tested blood MO from 22 patients with aplastic anemia (AA) for their capacity to undergo terminal maturation in vitro. After isolation, blood MO in six patients expressed CD14 molecules at low density when compared to normals. On culture for 7 days, in 15 patients various abnormalities could be shown by phenotype analysis using cell-enzyme-linked immunosorbent assay (ELISA) and an immunoperoxidase staining technique of single cells. Abnormalities ranged from the distinctive failure of mature MAC to express single surface antigens (eg, gp64-MAX.1) to complete inhibition of the development of a MAC maturation-associated phenotype. In three patients the maturational defect was found to persist in complete remission after successful therapy with antileukocyte globulin (ALG). Neither in other immunosuppressed or multiple-transfused patients nor in those with bone marrow hypoplasia secondary to cancer chemotherapy and during hematologic reconstitution following autologous bone marrow transplantation (BMT), defective MO maturation in vitro was seen. Our data provide evidence for the existence of serious disorders within the MO-MAC lineage in patients with AA. This observation may either reflect the stem-cell defect or indicate a MAC involvement in the pathogenesis of the disease.
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PMID:Defective monocyte-to-macrophage maturation in patients with aplastic anemia. 280 53

Activation-associated antigens such as CD11b, CD14 and CD64 of neutrophils have been reported. Although CD48 is an activation antigen of lymphocytes and monocytes, whether it is an activation antigen of neutrophils has not previously been examined. Herein, using FACS analysis, we examined the expression of surface CD48 on neutrophils activated in vivo by G-CSF administered for the treatment of idiopathic aplastic anemia. CD48 expression was increased 24 h after the initial G-CSF infusion and peaked within 1 week. Within a few days after discontinuation of G-CSF administration, it returned to the pretreatment level. This indicates that CD48 is an activation antigen of neutrophils.
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PMID:Increased expression of CD48 on neutrophils activated in childhood patients with aplastic anemia. 753 99

The association of paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia (AA) raises the yet unresolved questions as to whether these two disorders are different forms of the same disease. We compared two groups of patients with respect to cytogenetic features, glycosylphosphatidylinositol (GPI)-linked protein expression, protein C/protein S/thrombomodulin/antithrombin III activity, and PIG-A gene expression. The first group consisted of eight patients with PNH (defined as positive Ham and sucrose tests at diagnosis), and the second, 37 patients with AA. Twelve patients with AA later developed a PNH clone. Monoclonal antibodies used to study GPI-linked protein expression (CD14 [on monocytes], CD16 [on neutrophils], CD48 [on lymphocytes and monocytes], CD67 [on neutrophils and eosinophils], and, more recently, CD55, CD58, and CD59 [on erythrocytes]) were also tested on a cohort of 20 normal subjects and five patients with constitutional AA. Ham and sucrose tests were performed on the same day as flow-cytometric analysis. Six of 12 patients with AA, who secondarily developed a PNH clone, had clinical symptoms, while all eight patients with PNH had pancytopenia and/or thrombosis and/or hemolytic anemia. Cytogenetic features were normal in all but two patients. Proteins C and S, thrombomodulin, and antithrombin III levels were within the normal range in patients with PNH and in those with AA (with or without a PNH clone). In patients with PNH, CD16 and CD67 expression were deficient in 78% to 98% of the cells and CD14 in 76% to 100%. By comparison, a GPI-linked defect was detected in 13 patients with AA, affecting a mean of 32% and 33% of CD16/CD67 and CD14 cell populations, respectively. Two of three tested patients with PNH and 1 of 12 patients with AA had a defect in the CD48 lymphocyte population. In a follow-up study of our patient cohort, we used the GPI-linked molecules on granulocytes and monocytes investigated earlier and added the study of CD55, CD58, and CD59 on erythrocytes. Two patients with PNH and 14 with AA were studied for 6 to 13 months after the initial study. Among patients with AA, four in whom no GPI-anchoring defect was detected in the first study had no defect in follow-up studies of all blood-cell subsets (including erythrocytes). Analysis of granulocytes, monocytes, and erythrocytes was performed in 7 of 13 AA patients in whom affected monocytes and granulocytes were previously detected. A GPI-anchoring defect was detected on erythrocytes in five of six.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link. 785 65

The clinical interrelationship between paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia (AA) promoted a search for a pathogenetic link. Since the molecular defect in PNH is a failure to express phosphatidylinositol glycan-anchored proteins (PIG-AP), we investigated whether this defect could also be demonstrated on peripheral blood cells of patients with typical AA. Quantification of the expression of PIG-AP was performed by flow cytometry using the monoclonal antibodies (MAbs) CD16 and CD66b for granulocytes, CD14 and CD48 for monocytes, CD48 and CD52 for lymphocytes, and CD55 and CD59 for erythrocytes. We analyzed cells from 52 patients with acquired AA. A PIG-AP-defective population was identified in 27 of 52 patients (52%) in at least one cell lineage. Granulocytes were involved in 25 of 27, monocytes in 18 of 25, lymphocytes in seven of 27, and erythrocytes in seven of 27 AA patients who were affected by a PIG-AP deficiency. The response rate to standard immunosuppressive therapy was significantly higher in the group of patients without a PIG-AP-deficient population than in patients with a PIG-AP-deficient population in at least one cell lineage (85.7 vs. 30.4%; p < 0.0003). Our results demonstrate that on the basis of PIG-AP expression, the proportion of AA patients who show features of typical AA along with a PNH phenotype is substantially higher than previously recognized. The pattern of PIG-AP expression might identify subgroups of AA patients who differ in the underlying mechanism as well as in the course of their disease.
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PMID:A pathogenetic link between aplastic anemia and paroxysmal nocturnal hemoglobinuria is suggested by a high frequency of aplastic anemia patients with a deficiency of phosphatidylinositol glycan anchored proteins. 799 74

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder of hematopoiesis in which affected cells are deficient in glycosylphosphatidyl-inositol (GPI) anchored surface proteins. The authors used flow cytometry to study 10 patients with PNH. They used a comprehensive panel of monoclonal antibodies against all nine currently known GPI-linked surface proteins (CD14, CD16, CD24, CD48, CD55, CD58, CD59, CD67, CD73) on cells of various lineages. Deficient cells were identified in the granulocytic-monocytic and erythroid lineages in all patients. However, the lymphoid lineage was affected in only eight patients. The patterns of deficiency were variable, with deficient cells constituting a part to all of the cells in the lineages tested. Certain proteins, including CD16, CD58, and CD59, appeared to be preferentially expressed, despite severe deficiencies of other GPI-linked proteins. Moreover, a trimodal pattern of expression of CD16, CD48, and CD59 was observed, in which a population of cells with intermediate levels of expression were identified in addition to positive and deficient cells. The authors' findings indicated a great degree of heterogeneity in the patterns and levels of expression of the GPI-linked proteins in the various cell types, as well as a possible heterogeneity in lineage involvement. The different patterns of expression of GPI-linked proteins should be considered when using flow cytometry to diagnose PNH. Finally, the clinical progression in some of the patients suggested a possible link between PNH, aplastic anemia, and myelodysplasia.
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PMID:Flow cytometric measurement of glycosylphosphatidyl-inositol-linked surface proteins on blood cells of patients with paroxysmal nocturnal hemoglobinuria. 803 65

Paroxysmal nocturnal hemoglobinuria (PNH) results from somatic mutations in the PIG-A gene, leading to poor presentation of glycosylphosphatidylinositol (GPI)-anchored surface proteins. PNH frequently occurs in association with suppressed hematopoiesis, including frank aplastic anemia (AA). The relationship between GPI-anchored protein expression and bone marrow (BM) failure is unknown. To assess the hematopoietic defect in PNH, the numbers of CD34+ cells, committed progenitors (primary colony-forming cells [CFCs]), and long-term culture-initiating cells (LTC-ICs; a stem cell surrogate) were measured in BM and peripheral blood (PB) of patients with PNH/AA syndrome or patients with predominantly hemolytic PNH. LTC-IC numbers were extrapolated from secondary CFC numbers after 5 weeks of culture, and clonogenicity of LTC-ICs was determined by limiting dilution assays. When compared with normal volunteers (n = 13), PNH patients (n = 14) showed a 4.7-fold decrease in CD34+ cells and an 8.2-fold decrease in CFCs. LTC-ICs in BM and in PB were decreased 7.3-fold and 50-fold, respectively. Purified CD34+ cells from PNH patients had markedly lower clonogenicity in both primary colony cultures and in the LTC-IC assays. As expected, GPI-anchored proteins were decreased on PB cells of PNH patients. On average, 23% of monocytes were deficient in CD14, and 47% of granulocytes and 58% of platelets lacked CD16 and CD55, respectively. In PNH BM, 27% of CD34+ cells showed abnormal GPI-anchored protein expression when assessed by CD59 expression. To directly measure the colony-forming ability of GPI-anchored protein-deficient CD34+ cells, we separated CD34+ cells from PNH patients for the GPI+ and GPI-phenotype; CD59 expression was chosen as a marker of the PNH phenotype based on high and homogeneous expression on fluorescent staining. CD34+ CD59+ and CD34+ CD59-cells from PNH/AA patients showed similarly impaired primary and secondary clonogeneic efficiency. The progeny derived from CD34+ CD59- cells were both CD59- and CD55-. A very small population of CD34+ CD59- cells was also detected in some normal volunteers; after sorting, these CD34+ CD59- cells formed normal numbers of colonies, but their progeny showed lower CD59 levels. Our results are consistent with the existence of PIG-A-deficient clones in some normal individuals. In PNH/AA, progenitor and stem cells are decreased in number and function, but the proliferation in vitro is affected similarly in GPI-protein-deficient clones and in phenotypically normal cells. As measured in the in vitro assays, expansion of PIG-A- clones appears not be caused by an intrinsic growth advantage of cells with the PNH phenotype.
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PMID:Impaired hematopoiesis in paroxysmal nocturnal hemoglobinuria/aplastic anemia is not associated with a selective proliferative defect in the glycosylphosphatidylinositol-anchored protein-deficient clone. 902 39

Refractory anemia (RA) in myelodysplastic syndrome (MDS) without prominent dysplasia closely resemble the mild type of aplastic anemia (AA) in their hematological features. This sometimes makes it difficult to distinguish clearly between the two diseases. Using the multi-color flow cytometric technique, we compared cell surface antigen expression patterns on bone marrow hematopoietic progenitor cells which were isolated as a CD34 positive- CD45 dull positive with low side scatter intensity (CD34(+)CD45(dull+)SSC(low)) population in flow cytogram between RA (n=12) and AA (n=11). The antigens analyzed in CD34(+)CD45(dull+)SSC(low) mononuclear cells were: CD38 and CD71 for cell growth-related antigens, CD 33 and CD13 for myeloid and monocytoid lineage-associated antigens, CD7 and CD19 for lymphoid lineage, and CD14 for a monocytic lineage specific antigen. The percentages of CD34(+)CD45(dull+)SSC(low) cells in bone marrow non-erythroid mononuclear cells, and the expression frequencies of CD38, CD71, CD33 and CD13 antigens in CD34(+)CD45(dull+)SSC(low) progenitors were all significantly decreased in AA compared to normal bone marrows (n=7) (P<0.005). In contrast, in RA bone marrows the percentages of CD34(+)CD45(dull+)SSC(low) cells showed wide distribution and the cell surface antigen expression patterns varied among each case: some cases showed low frequencies of CD38 and CD71 expression as well as AA, whereas the others showed high expression frequency of specific antigen(s) which may reflect the clonal expansion of an abnormal clone in bone marrow. An MDS patient who had progressed from RA to RAEB showed further projecting pattern of expression of CD38 and CD33 in CD34(+)CD45(dull+)SSC(low) population in accordance with the disease progression. These data suggest that analysis of cell surface antigen expression patterns of CD34(+)CD45(dull+)SSC(low) progenitor cells by multi-color flow cytometry appears to be a useful method for qualitative and quantitative assessment of marrow progenitor states in AA and RA, therefore this method could be helpful for early detection of clonal evolution in MDS.
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PMID:Comparative multi-color flow cytometric analysis of cell surface antigens in bone marrow hematopoietic progenitors between refractory anemia and aplastic anemia. 1086 34

The expansion of paroxysmal nocturnal hemoglobinuria (PHN) clone was evaluated in a patient with aplastic anemia (AA) of 18 years of evolution during an hemolytic crisis. On day 0, Ham and Sucrosa tests were positive and hematological parameters were altered. Low hemoglobin (Hb) levels and erythrocyte and leukocyte counts were found and continued decreasing on days 7 and 24 (last day of study). High LDH levels, indirect bilirubin and reticulocyte counts were detected throughout. We evaluated CD55 and CD59 on erythrocytes by flow cytometry. Our results showed low CD55 expression with respect to the normal pattern. Since day 0, CD59 staining detected two red cell populations: PNH I (48%), cells with positive fluorescence similar to normal and PNH III (52%), negative cells (PNH clone). These negative cells increased, reaching 70% on day 24. Other membrane anchored leukocyte proteins were also absent (CD14) or decreased (CD16). We found a good correlation between clinical observations, evolution of the laboratory values and expansion of the PNH clone.
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PMID:[Evolution of paroxysmal nocturnal hemoglobinuria clone during an hemolytic crisis in a patient with aplastic anemia. Flow cytometry study]. 1172 26

Antithymocyte globulin (ATG) and antilymphocyte globulin (ALG) are currently used successfully for immunosuppressive treatment of aplastic anemia. In this study we have investigated whether commercial ATG/ALG preparations contain antibodies against glycosylphosphatidyl-inositol anchored proteins (GPI-AP), which could be responsible for emergence of GPI-deficient populations in aplastic anemia after ATG/ALG therapy. We analyzed four commercial ATG/ALG preparations by competitive binding assays using flow cytometry. Quantification was achieved by calculating the concentration of ATG/ALG required to give 50% inhibition of binding the specific fluorochrome-labeled monoclonal antibody (EC50). High concentrations of antibodies against the GPI-anchored protein CD52 were found in all preparations (Lymphoglobulin Genzyme, Thymoglobulin Genzyme, ATGAM. Pharmacia & Upjohn, and ATG-Fresenius S Fresenius). Antibodies against the GPI-anchored protein CD48 are present in significant concentrations except in the preparation ATGAM. CD16 antibodies were found in lower concentrations. We could not detect significant concentrations of antibodies against the GPI-anchored proteins CD157 and CD14. Campath-1H, a monoclonal antibody against the GPI-anchored protein CD52, has been used as immunosuppressive tool for T-cell depletion. CD52 antibodies in ATG/ALG preparations might contribute in the same way to the immunosuppressive effects in treatment of aplastic anemia. It is known that in a substantial proportion of patients with aplastic anemia GPI-deficient cells are present in a low level at diagnosis or emerge after immunosuppressive therapy. GPI-anchored antibodies in ATG/ALG preparations might lead to a relative advantage for pre-existing GPI-deficient cells caused by an escape from the antibody-mediated attack.
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PMID:Antibodies to glycosylphosphatidyl-inositol anchored proteins (GPI-AP) in antithymocyte and antilymphocyte globulin: possible role for the expansion of GPI-AP deficient cells in aplastic anemia. 1913 53

Diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) with flow cytometry traditionally involves the analysis of CD55 and CD59 on RBCs and neutrophils. However, the ability to accurately detect PNH RBCs is compromised by prior hemolysis and/or transfused RBCs. Patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS) can also produce PNH clones. We recently described a multiparameter fluorescent aerolysin (FLAER)-based flow assay using CD45, CD33, and CD14 that accurately identified PNH monocyte and neutrophil clones in PNH, AA, and MDS. Here, we compared the efficiency of this WBC assay with a CD59-based assay on RBCs during a 3-year period. PNH clones were detected with the FLAER assay in 63 (11.8%) of 536 samples tested, whereas PNH RBCs were detected in only 33 (6.2%), and always with a smaller clone size. The FLAER assay on WBCs is a more sensitive and robust primary screening assay for detecting PNH clones in clinical samples.
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PMID:Use of a FLAER-based WBC assay in the primary screening of PNH clones. 1976 34

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