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)

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired blood disorder thought to result from a somatic mutation in a hemopoietic stem cell. PNH may evolve to aplastic anemia or to acute leukemia. PNH cells are deficient in proteins attached to the cell membrane via a glycosylphosphatidylinositol structure, called the GPI anchor, and the primary lesion in PNH is thought to be a defect in the biosynthesis of the GPI anchor. We have recently established permanent lymphoblastoid cell lines that have the PNH phenotype and we report now the isolation of human-human somatic cell hybrid clones obtained by fusing them with normal lymphoblastoid cells. In all of 21 hybrid clones, obtained from five different patients, the expression of three different GPI-linked proteins on the hybrid cells was normal. These findings indicate that the PNH mutant gene is recessive with respect to the normal allele and that a recessive mutation can cause a clonal preneoplastic disorder.
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PMID:Paroxysmal nocturnal hemoglobinuria: correction of abnormal phenotype by somatic cell hybridization. 851 71

Twenty-six consecutive patients with acquired aplastic anaemia (AA) and nine patients with de novo paroxysmal nocturnal haemoglobinuria (PNH) were included in this study. In these 35 patients a GPI-anchored molecule defect at the platelet surface was investigated by flow-cytometry. Platelets from eight out of the nine patients with de novo PNH were found to be deficient for the GPI-anchored molecule CD55, CD58 and CD59. We also detected a GPI-anchored molecule defect on monocytes, granulocytes, and erythrocytes in all patients with de novo PNH. Among the 26 AA patients, a GPI defect was detected on platelets in five patients. Interestingly, these five patients were also found to have a GPI-anchored molecule defect on erythrocytes, whereas in 10 patients the GPI-anchored molecule defect was only detected on monocyte and polymorphonuclear (PMN) cells.
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PMID:Aplastic anaemia and paroxysmal nocturnal haemoglobinuria: a study of the GPI-anchored proteins on human platelets. 865 77

We used CD55 and CD59 monoclonal antibodies (mAbs) for the investigation of peripheral blood cells from sixteen patients with paroxysmal nocturnal haemoglobinuria (PNH) by flow cytometry. Mixed-field populations of erythrocytes, platelets, monocytes or granulocytes were visualized in all cases but, due to the extended half-life of unaltered erythrocytes and blood transfusions, the GPI-linked protein deficiency was more obvious for white blood cells, especially granulocytes, and platelets. In contrast, a minority of altered lymphocytes was observed in only five patients. The expression of CD55 and CD59 antigens was grossly correlated but quantitative differences were observed for patients whose cells were only partially deficient in GPI-linked proteins. Patients with PNH secondary to aplastic anaemia exhibited a significantly lower percentage of altered cells compared with "classical" PNH patients. In addition, we found that CD58 normally bound to deficient white blood cells and platelets, showing the LFA-3 molecule is expressed as a transmembrane protein in these cells.
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PMID:Expression of glycosyl-phosphatidylinositol-linked glycoproteins in blood cells from paroxysmal nocturnal haemoglobinuria patients: a flow cytometry study using CD55, CD58 and CD59 monoclonal antibodies. 890 82

A large fraction of the hematopoietic cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) are deficient in membrane expression of glycosylphosphatidylinositol-anchored proteins (GPI-APs). Current evidence suggests that this deficiency is sufficient to account for the hemolytic and thrombotic manifestations of this disease but not for its frequent association with aplastic anemia, an autoimmune disorder in which the patients' own hematopoietic progenitor cells are the target. Mutations in X-linked gene PIG-A, encoding one of several enzymes required for the biosynthesis of the glycophosphatidylinositol anchor, have been found in all PNH patients studied to date. Recent experiments with murine Pig-a knock-out embryonic stem cells show that although embryogenesis is critically dependent on normal GPI-AP expression, Pig-a-deficient cells can undergo apparently normal hematopoietic differentiation if they develop in a GPI-AP-replete environment. Thus, in an in vitro mouse model of PNH, Pig-a mutations confer no gross proliferative or differentiative advantage or disadvantage, suggesting an unidentified process selecting for these mutations in the bone marrow of patients with the PNH-aplastic anemia syndrome. The rescue of hematopoiesis observed in chimeric cultures of knock-out and normal cells was accompanied by intercellular transfer of GPI-AP, suggesting exciting new possibilities for future therapeutic manipulations in PNH patients.
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PMID:Paroxysmal nocturnal hemoglobinuria: new insights from murine Pig-a-deficient hematopoiesis. 906 78

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

The review outlines developments in research on paroxysmal nocturnal haemoglobinuria (PNH). The disease is due to a somatic mutation of the PIG-A gene. This results in deficiency of the protein, GPI (glucosyl phosphatidyl inositol), which serves as an anchor for several membrane-bound proteins including MIRL (CD59; membrane inhibitor of reactive lysis) and DAF (CD55; decay accelerating factor). The absence of these proteins results in increased cellular sensitivity to complement-mediated lysis, affecting not only red cells, leukocytes and platelets, but also haemopoietic stem cells. This explains the often complex clinical picture in PNH (haemolysis, pancytopenia and increased thrombotic predisposition), and the well known relationship between PNH and aplastic anaemia.
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PMID:[PNH--paroxysmal nocturnal hemoglobinuria. An old disease explained by new technology]. 942 27

The peripheral blood cells of ten patients with biopsy-proven aplastic anemia were studied by means of flow-cytometry in order to assess the expression of two phosphatidylinositol-anchored surface proteins: CD55/DAF (decay accelerating factor) and CD59/MIRL (membrane inhibitor of reactive lysis). An abnormal expression was found in five of these ten patients, whereas the "traditional" tests for paroxysmal nocturnal hemoglobinuria (PNH) were positive only on two of these five individuals. Five of the aplastic patients were treated with anti-thymocyte globulin and cyclosporin-A and three entered a complete remission; of the latter, one had CD55/CD59 deficiencies whereas two did not. Along the study period one patient with a hemolytic pattern of PNH was identified. It is concluded that CD55 and/or CD59 abnormalities are frequent in Mexican mestizo patients with aplastic anemia, that the aplastic presentation of PNH is more frequent in Mexico than the hemolytic presentation, that the flow-cytometric identification of CPI-anchored proteins is more sensitive than the "traditional" PNH tests, and that some patients with PNH-aplasia may respond to intensive immunosuppressive treatment. The flow-cytometric identification of GPI-anchored cell surface proteins should replace the "traditional" tests in the identification of patients with PNH.
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PMID:[Glycosilphosphatidylinositol-anchored cell surface protein deficiency in Mexican mestizo patients with aplastic anemia]. 1034 61

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

Acquired somatic mutations of the PIG-A gene lead to deficient expression of glycosyl-phosphatidyl-inositol-anchored proteins (GPI-AP) by haematopoietic cells and play a causative role in the pathogenesis of paroxysmal nocturnal haemoglobinuria (PNH). However, PIG-A mutations do not explain how the defective PNH clone can expand. It was hypothesized that a selection process conferring a relative advantage to the GPI-AP-deficient population is required. Since GPI-AP-deficient cells are also detectable in a substantial proportion of patients with otherwise typical aplastic anaemia (AA), the mechanisms inducing bone marrow failure might selectively spare the GPI-deficient cells. In order to examine the growth characteristics of GPI-AP-deficient cells in more detail, we performed repeated analyses of GPI-AP expression on peripheral blood cells in 41 patients with AA. We observed four patterns of the course of GPI-AP-deficient populations: (1) 13 patients showed normal expression of GPI-AP in the first analysis and in at least two follow-up studies at a median time of 709 days after the first analysis. (2) Secondary evolution of a GPI-AP-deficient population was a rare event. Only 4 patients with initially normal GPI-AP expression developed a GPI-AP-deficient population during follow up after immunosuppressive treatment. (3) Persistence of GPI-AP-deficient cells was observed in 16 patients during a median follow-up time of 774 days. However, in some patients, the size of the GPI-AP-deficient population increased substantially. (4) Disappearance of a GPI-AP-deficient population was observed in 8 patients. The time course of GPI-AP expression in relation to the treatment suggests that therapeutic interventions might modulate the ratio of normal versus GPI-AP-deficient haematopoiesis. Overall, these data argue against an 'absolute growth advantage' of GPI-AP-deficient cells. Our data are consistent with the hypothesis that haematopoietic failure caused by damage to normal haematopoiesis allows the outgrowth of a GPI-AP-deficient population. Thus, in at least some patients GPI-AP-deficient cells might pre-exist at a very low percentage and replace haematopoiesis after an insult to the normal cells.
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PMID:Paroxysmal nocturnal haemoglobinuria: a replacement of haematopoietic tissue? 1070 58

Paroxysmal nocturnal hemoglobinuria is an acquired clonal disorder of the hematopoietic stem cell in which intravascular hemolysis is due to an intrinsic defect in the membrane of red cells that makes them increasingly susceptible to lysis by complement. The phenotypic hallmark of PNH cells is an absence or marked deficiency of GPI-anchored proteins such as CD 59+, CD 55+ and others which normally protect cells from the action of complement. PHN is closely associated with aplastic anemia. Some degree of bone marrow failure is always present. Management of PNH is complicated by a highly variable clinical picture and course. Some patients have severe anemia aggravated by hemolytic crises and associated thromboses. Bone marrow failure is accompanied with frequent infections and hemorrhagic manifestations due to thrombocytopenia. With the exception of marrow transplantation, no definite therapy is available. In the exceptional circumstance in which the patient has a syngeneic twin, bone marrow transplantation is the most appropriate therapy for severe PNH because of absence of graft-versus-host disease. In general syngeneic transplantation without preconditioning has been unsuccessful because abnormal hematopoiesis returns. Allogeneic bone marrow transplantation has been used, but the transplant-associated morbidity and mortality are high due mainly to the fatal graft-versus-host disease and severe posttransplant marrow failure. Use of an unrelated donor transplant has to be considered as contraindicated. PNH is associated with striking predisposition to intravascular thrombosis which often involves the portal system or the brain. Fatal thromboses account for about 40-50% of all deaths in patients with PNH. The etiology of the thrombophilia in PNH is not fully clarified. Anticoagulation or thrombolytic therapy is required for treatment of venous thrombosis, the latter vena cava. Prophylactic anticoagulation in patients without contraindications such as severe thrombocytopenia seems to be justified. However, whether such therapy may be efficacious in reducing the incidence of thromboses or affect survival is conjectural. PNH patients have varying degree of platelet activation and some authors suggest that antiplatelet therapy might be efficacious in reducing the incidence and severity of venous thrombosis in PNH. Pregnancy is hazardous. Female patients should avoid the use of oral contraceptives. Pregnant patients require combined care of an experienced hematologist and obstetrician specialized in the management of high-risk pregnancies.
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PMID:[Treatment of paroxysmal nocturnal hemoglobinuria (PNH)]. 1182 54


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