Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002874 (aplastic anemia)
 5,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate quality of hematologic recovery in aplastic anemia (AA) patients treated with cyclosporine A (CyA), we examined polymorphonuclear leukocytes (PMNCL) from 25 AA patients for clonality and glycosyl-phosphatidylinositol (GPI)-anchored membrane protein expression. Using three different X-linked gene probes, we failed to detect clonal hematopoiesis in seven CyA-responsive female patients. Clonal hematopoiesis was detected in two of six female patients refractory to CyA therapy, although one of these two patients had shown monoclonality before therapy. Flow-cytometric analysis revealed a normal expression of GPI-linked membrane proteins, including CD55, CD59, and CD16 on PMN in all patients treated with CyA, irrespective of response, except for one patient who had a small proportion of GPI-anchored membrane protein-negative cells before therapy. The proportion remained unchanged 41 months after hematologic recovery following CyA therapy. These findings suggest that successful therapy of AA with CyA may not be associated with a significant risk of developing late clonal complications, such as paroxysmal nocturnal hemoglobinuria (PNH) and myelodysplasia.
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PMID:Quality of hematologic recovery in patients with aplastic anemia following cyclosporine therapy. 753 14

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

CD16 antibodies recognize Fcgamma receptors III of a and b types. In a patient with severe idiopathic aplastic anaemia (AA), polymorphonuclear cells, which in normal subjects express FcgammaRIIIb, were found to be CD16 negative. The FcgammaRIIIb gene configuration was analysed by PCR on peripheral blood mononuclear cells. Bi-allelic deletion encompassing at least part of the coding exon 5 was found in the patient and his brother, suggesting a hereditary defect. The patient underwent successful bone marrow transplantation from his HLA-matched brother despite a similar phenotype and genotype. This observation suggests that FcgammaRIIIb hereditary deficiency in donor and/or recipient does not impair engraftment and justifies the use of other monoclonal antibodies in addition to CD16 in the study of GPI-anchored antigen expression.
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PMID:Aplastic anaemia in a case of hereditary neutrophil Fcgamma receptor IIIb deficiency. 937 66

Expression of alkaline phosphatase (ALP) on the surface membrane of neutrophils (mNAP) was studied by immunofluorescence using an anti-ALP monoclonal antibody. Fluorescent intensity distribution of mNAP was analyzed using FACS (fluorescence-activated cell sorter). The mean fluorescent intensity (MFI) of the mNAP in this assay was well correlated with the neutrophil ALP (NAP) score demonstrated cytochemically (r = 0.832). mNAP levels in various hematological disorders were evaluated by % mNAP+ cells and MFI. The levels in aplastic anemia and polycythemia vera were significantly higher, and in chronic myelocytic leukemia and paroxysmal nocturnal hemoglobinuria (PNH), the levels were significantly lower compared with the levels in healthy volunteers. Two-color immunofluorescence with anti-ALP and anti-CD16 showed that the PNH clone was essentially negative for mNAP, whereas residual normal neutrophils (CD16+) had levels slightly higher than those in normal individuals. Highly reproducible results were obtained in the blood samples which were stored at 4 degrees C for at least 24 hr without any treatment prior to immunofluorescent staining. No degradation of fluorescent intensity was seen 4 days after staining and fixation. The mNAP assay is simple, without subjective evaluation for quantification, and is useful for differential diagnosis of hematological disorders.
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PMID:Assessment of alkaline phosphatase on the surface membrane of neutrophils by immunofluorescence. 988

WHAT IS HYPOPLASTIC ANEMIA? Aplastic anemia is a hematological disease characterized by pancytopenia and bone marrow hypoplasia. Acquired cases of aplastic anemia are almost all idiopathic and arise from unknown causes. Other cases of aplastic anemia are secondary and are caused by radiation, chemicals or viruses. PATHOPHYSIOLOGY: Aplastic anemia is manifested as a marked reduction in the number of pluripotent hematopoietic stem cells, but why this occurs is still uncertain. Some of the proposed causes include abnormalities of the hematopoietic stem cells, abnormalities in the hematopoietic microenvironment, and immunologically mediated damage to the hematopoietic stem cells (Figure 1). ABNORMALTIES OF THE HEMATOPOIETIC STEM CELLS: Patients with aplastic anemia, and long-term survivors in particular, are at increased risk of developing paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), or acute myelocytic leukemia. This suggests that, in at least some of these patients, the hematopoietic stem cells themselves are abnormal. It also suggests that in some of these patients the blood cells are clonal (that is, all the blood cells are derived from a single pluripotent stem cell). In short, what these findings imply is that aplastic anemia may be caused by the emergence of an abnormal clone. Clonal hematopoiesis, however, can also be considered nothing more than a consequence. In other words, it is possible that hematopoiesis in this kind of patient is performed by a lone pluripotent stem cell that somehow managed to survive eradication. No definitive interpretation of clonal hematopoiesis has been agreed upon, and it is still a topic for future research. ABNORMAL HEMATOPOIETIC MICROENVIRONMENT: The presence of stromal cells, which form the microenvironment of bone marrow, is very important in hematopoiesis. Hematopoietic stem cells proliferate and differentiate either by adhering to stromal cells or by being stimulated by the various hematopoietic factors that stromal cells produce. Therefore, it is quite possible that aplastic anemia is caused by abnormalities in the hematopoietic microenvironment. However, many separate studies have demonstrated that the hematopoietic microenvironment in the vast majority of aplastic anemia cases is normal. IMMUNE MECHANISMS: Immunosuppressive agents are often effective in treating aplastic anemia, and therefore it is believed that immunological mechanisms contribute to the disease in more than half the cases. The following mechanisms have been proposed as causes for the onset of immunologically mediated aplastic anemia: * Decreases in Hematopoietic Factors Produced by Monocytes and Lymphocytes. Some patients with aplastic anemia show decreased production of interleukin 1 (IL-1) by peripheral blood monocytes, and it is possible that a drop in the concentration of this factor is linked to the onset of the disease [1]. It is also possible, however, that decreased IL-1 production by monocytes is not a cause of the disease, but merely a consequence. Moreover, no cases have been reported that exhibit reduced production of hematopoietic factors produced by lymphocytes such as GM-CSF, IL-3, or IL-6. * Damage by Cytokines that Suppress Hematopoiesis. It has been reported that increased levels of interferon &ggr; (IFN-&ggr;), which is produced by lymphocytes, and tumor necrosis factor &agr; (TNF-&agr;), which is produced by monocytes and macrophages, are found in the bone marrow and peripheral blood of aplastic anemia patients [2, 3]. These two factors act as suppressors of hematopoiesis, and it is possible that they contribute to the disease. The increase of these inflammatory cytokines in the bone marrow strongly suggests the presence of either specific or non-specific destruction of the hematopoietic stem cells by immunoregulatory cells. * Suppression of Hematopoiesis by Cytotoxic T Cells (Killer T Cells). Cases have been reported in which cytotoxic T cell clones that damage the autologous hematopoietic precursor cells are present [4]. Therefore, we can easily conceive of a mechanism in which these cytotoxic T cells specifically destroy the hematopoietic stem cells and cause aplastic anemia. * Suppression of Hematopoiesis by Natural Killer (NK) Cells. NK activity of aplastic anemia patients is depressed, and, generally speaking, it is highly unlikely that NK cells contribute to this condition. However, it has been reported that clonal NK cells are thought to cause the disease in patients exhibiting pancytopenia and bone marrow hypoplasia. Therefore, when this disease is diagnosed, a peripheral blood granular lymphocyte count and NK cell surface marker analysis should always be performed. DIAGNOSIS: A necessary condition for the diagnosis of aplastic anemia is the presence of pancytopenia. Moreover, it is necessary to rule out all other causes of pancytopenia. It is especially important in differential diagnosis to look for PNH and MDS. In cases of aplastic anemia there are patients that exhibit PNH during the course of the disease, and this condition is called aplastic anemia-PNH syndrome. It has recently been shown that bone marrow and peripheral blood cells in some patients diagnosed with aplastic anemia are partially lacking GPI anchor proteins (CD16, CD55, and CD59) [5]. Whether such patients become to exhibit aplastic anemia-PNH syndrome in the future remains to be elucidated. In MDS the bone marrow generally exhibits normoplasia or hyperplasia, and only in rare cases does it exhibit hypoplasia. This condition is referred to as hypoplastic MDS. Hypoplastic MDS can be differentiated from aplastic anemia by the presence of abnormal cell morphology that is sometimes accompanied by chromosomal abnormalities. TREATMENT:Aplastic anemia is treated with androgens, high-dose methylprednisolone, cyclosporin A (CyA), antithymocyte globulin (ATG), antilymphocyte globulin (ALG), hematopoietic growth factors such as G-CSF, and bone marrow transplantation. Interestingly, patients who require continuous CyA administration to maintain stable hematopoiesis have a specific HLA class II haplotype (DRB1*1501-DQA1*0102-DQB1*0602) [6]. Recent reports from EBMT SAA Working Party showed the excellent therapeutic result (response rate 82%) when severe cases were treated with ALG, CyA and G-CSF in combination [7].
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PMID:Special Education: Aplastic Anemia. 1038 86

Chronic natural killer cell lymphocytosis is a persistent state of natural killer (NK) cell (CD3-CD16/CD56+) excess in the peripheral blood that is not associated with clinical lymphoma. In 16 consecutive patients (median age 60.5 years, range 7-77), males were overrepresented (M:F 7:1) and the median absolute NK cell count was 4.09 x 10(9)/l (range 1.2-16.6). Bone marrow examination was performed in 14 patients and showed atypical granulomata in two; chromosome studies in seven patients were normal. Clonal T-cell receptor gene rearrangement was not found in any of 12 patients evaluated. At presentation, seven patients (44%) had no clinical symptoms or signs and the others had vasculitic skin lesions (three patients), non-neutropenic fever (three patients), recurrent neutropenic infection (two patients), musculoskeletal symptoms (two patients), peripheral neuropathy (two patients), aphthous ulcers (one patient), and splenomegaly (one patient). Five patients had anaemia, five had neutropenia, and two had thrombocytopenia. After a median follow-up of 5.1 years (range 0-10.2) from immunophenotypic diagnosis or 5.7 years (range 0.1-14.1) from documentation of absolute lymphocytosis, vasculitic glomerulonephritis developed in one patient, accelerated splenomegaly developed in a patient receiving myeloid growth factor treatment, and severe aplastic anaemia developed in one patient. Treatment with nonsteroidal anti-inflammatory drugs or immunosuppressive agents was variably successful.
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PMID:A long-term study of patients with chronic natural killer cell lymphocytosis. 1051 98

Chronic natural killer (NK) lymphocytosis involves a persistent increase in CD56+ large granular lymphocytes (LGLs) that is sometimes associated with immune-mediated complications, such as anemia and neutropenia. However, aplastic anemia (AA) is a rare complication. Here we describe 2 patients with severe AA who presented with persistent increases in NK cells. Their LGLs were positive for CD56, CD16, and intracellular interferon (IFN)-gamma but negative for CD3, Fas-ligand, and T-cell receptor rearrangement, findings that are compatible with NK cells. Not only the number of NK cells, but NK activity as well, was increased in both patients. The number of NK cells changed according to hematologic recovery and relapse in 1 case. Thus, there seemed to be a close relationship between NK cells and the progression of AA, at least in this instance. Further investigation of the clinical course of similar cases and the characteristics of NK cells is necessary.
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PMID:Severe aplastic anemia associated with chronic natural killer cell lymphocytosis. 1119 12


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