Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002878 (hemolytic anemia)
 7,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic disorder characterized by complement-mediated hemolytic anemia, pancytopenia, and venous thrombosis. These clinical manifestations arise from an underlying molecular defect of bone marrow stem cells. Specifically, somatic mutations in the phosphatidylinositol glycan class A gene result in the ability of blood cells to anchor complement-regulatory proteins (CD59 and DAF) to the cell surface via glycosyl phosphatidylinositol (GPI). In an attempt to circumvent the functional defect in PNH cells, a recombinant transmembrane form of CD59 (CD59-TM) was analyzed for the ability to regulate complement activity. Balb/3T3 stable transfectants expressing similar levels of either CD59-TM or native CD59 (CD59-GPI) were equally protected against human complement-mediated membrane damage. Treatment of these cells with phosphatidylinositol-specific phospholipase C failed to release CD59-TM from the cell surface. Retroviral transduction of GPI-anchoring deficient mouse L cells with CD59-TM resulted in surface expression of the protein and rendered these cells resistant to human complement-mediated membrane damage. Conversely, L cells transduced with CD59-GPI failed to express this protein on the cell surface. A GPI-anchoring deficient complement-sensitive B-cell line derived from a PNH patient was successfully transduced with CD59-TM, resulting in surface expression of the protein. The PNH B cells expressing CD59-TM were protected against classical complement-mediated membrane damage by human serum. Taken together, these data establish that a functional recombinant transmembrane form of CD59 can be expressed on the surface of GPI-anchoring deficient PNH cells and suggest that retroviral gene therapy with this molecule could provide a treatment for PNH patients.
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PMID:Expression of recombinant transmembrane CD59 in paroxysmal nocturnal hemoglobinuria B cells confers resistance to human complement. 752 35

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

Paroxysmal nocturnal hemoglobinuria is an acquired clonal expansion of bone marrow stem cells that are deficient in the decay-accelerating factor, which is a complement regulatory glycoprotein (CD55), as well as in the membrane inhibitor of reactive lysis (CD59) and the C8-binding protein. These proteins are deficient on the membranes of red blood cells, granulocytes, monocytes, and platelets. The disorder is associated with intermittent hemolytic anemia, hemoglobinuria, infection, a tendency toward bone marrow aplasia, and venous thromboses. The thromboses, on resolution, may give rise to endothelial proliferation that may cause ischemia and ulceration, or, alternatively, the thromboses may cause ulceration leading to a granulation tissue response with exaggerated endothelial proliferation. We report a second case of paroxysmal nocturnal hemoglobinuria that presented roentgenographically as an ulcerated circumferential duodenal mass secondary to venous thrombosis accompanied by florid papillary endothelial hyperplasia. We also review the literature concerning this phenomenon.
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PMID:Paroxysmal nocturnal hemoglobinuria associated with venous thrombosis and papillary endothelial hyperplasia presenting as ulcerated duodenal mass. 806 Feb 37

A 32-year-old man visited Kanto Teishin Hospital complaining of general fatigue in May, 1992. He had been diagnosed as having paroxysmal nocturnal hemoglobinuria since 1980, because of brownish urine in the morning. He received blood transfusion in 1980. In 1983, he was treated with medication. There was no remarkable improvement, however, and he stopped coming to the hospital. When he was admitted to our hospital, hemolytic anemia and hemosiderinuria were noticed. Sucrose hemolysis test and acidified-serum lysis test (Ham test) were both positive. Positive rates of decay accelerating factor and CD59 were 38.8% (control 100%) and 45.4% (control 100%), respectively. His diagnosis was thus confirmed. Bone marrow was slightly hypocellular, and erythroid cells were relatively hyperplastic (M/E ratio 0.68). The oral administration of iron and oxymetholone was not effective for anemia. He was treated with daily subcutaneous administration of recombinant human erythropoietin (EPO, 3,000U/body/day). His hemoglobin level increased from 7.5g/dl to 12.0g/dl in 4 weeks, and general fatigue disappeared. Since he had concurrent chronic hepatitis C, alpha-interferon was also administered and his hemoglobin level is now controlled between 10 and 11g/dl. This case suggests that EPO can be useful for treating hemolytic anemia, even though erythroid cells in the bone marrow are hyperplastic.
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PMID:[Improvement of anemia by recombinant human erythropoietin in paroxysmal nocturnal hemoglobinuria]. 823 Jul 45

Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic anemia caused by complement-mediated hemolysis. Blood cells from patients with PNH contain abnormal cells that lack complement regulatory proteins, DAF and CD59, both of which protect host cells from action of complement. DAF and CD59 are GPI-anchored and on the abnormal blood cells other GPI-anchored proteins are also deficient. A fundamental abnormality of PNH appeared to be deficient biosynthesis of the GPI-anchor at an early step. We cloned a cDNA of a gene termed PIG-A (for Phosphatidyl Inositol Glycan-class A) that encodes a 484 amino acid putative ER membrane protein which functions at that step and hence a responsible gene for PNH. Analysis of PIG-A transcripts in the abnormal cells from patients with PNH demonstrated various types of abnormalities such as decreased level of the transcript, splicing abnormality and mutations in the coding region. Thus, PNH is caused by a clonal expansion of abnormal blood cells derived from a hematopoietic stem cell bearing a somatic mutation occurred in PIG-A gene.
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PMID:[Recent advances in research on paroxysmal nocturnal hemoglobinuria]. 831 23

Paroxysmal nocturnal hemoglobinuria (PNH), an acquired clonal disorder is manifested by failure of hematopoietic cells to express phosphatidylinositol glycan-anchored proteins (PIG-AP). Since the PIG-A mutation is present at the stem cell level, all cell lines may be affected. Although the pathogenesis of hemolytic anemia in PNH is related to the absence of CD55 and CD59 molecules on the membrane of red cells, the mechanism responsible for the increased incidence of thrombotic events in PNH is not clear. In this study we measured two glycosylphosphatidylinositol (GPI)-linked molecules on platelets (CD55 and CD59) and two GPI-linked proteins on neutrophils (CD14 and CD16), comparing their expression on normal and PNH patients. Using two-color flow cytometric analysis with antibodies directed against CD42b and CD41a, we found that CD55 and CD59 were constitutively expressed by normal fresh platelets, but that the expression levels decreased during the five day storage of platelets. A substantial population of platelets lacking the GPI-linked proteins were detected in most cases. We demonstrated varying degrees of deficiency in the expression of GPI-anchored molecules with neutrophils, monocytes and platelets with the highest proportion of deficient cells found within monocytic lineage. Similar numbers of platelets with the PNH phenotype and normal platelets expressed activation markers before and after exposure to platelet agonists. Flow cytometry is more sensitive than Ham's test in monitoring expression of PNH in platelets. Differences in the numbers of circulating GPI-deficient platelets and myeloid cells suggest that either the survival of platelets and mature myeloid cells differs or megakaryocytopoeisis is abnormal within the GPI-deficient clone.
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PMID:Analysis of the expression of glycosylphosphatidylinositol anchored proteins on platelets from patients with paroxysmal nocturnal hemoglobinuria. 888 38

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disorder resulting from mutations in an X-linked gene, PIG-A, that encodes an enzyme required for the first step in the biosynthesis of glycosylphosphatidylinositol (GPI) anchors. PIG-A mutations result in absent or decreased cell surface expression of all GPI-anchored proteins. Although many of the clinical manifestations (e.g., hemolytic anemia) of the disease can be explained by a deficiency of GPI-anchored complement regulatory proteins such as CD59 and CD55, it is unclear why the PNH clone dominates hematopoiesis and why it is prone to evolve into acute leukemia. We found that PIG-A mutations confer a survival advantage by making cells relatively resistant to apoptotic death. When placed in serum-free medium, granulocytes and affected CD34(+) (CD59(-)) cells from PNH patients survived longer than their normal counterparts. PNH cells were also relatively resistant to apoptosis induced by ionizing irradiation. Replacement of the normal PIG-A gene in PNH cell lines reversed the cellular resistance to apoptosis. Inhibited apoptosis resulting from PIG-A mutations appears to be the principle mechanism by which PNH cells maintain a growth advantage over normal progenitors and could play a role in the propensity of this disease to transform into more aggressive hematologic disorders. These data also suggest that GPI anchors are important in regulating apoptosis.
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PMID:Resistance to apoptosis caused by PIG-A gene mutations in paroxysmal nocturnal hemoglobinuria. 923 50

Hemolytic anemia is a major feature of paroxysmal nocturnal hemoglobinuria (PNH). Intravascular red blood cell (RBC) destruction is caused by increased sensitivity of the abnormal erythrocyte to complement-mediated lysis, due to the GPI absence of a membrane-bound glycosylphosphatidylinositol (GPI)-linked protein, which functions as an inhibitor of reactive lysis (CD59). Both in vivo and in vitro models have suggested the feasibility of cell-to-cell transfer of GPI proteins, and patients with hemolysis could potentially benefit from transfer of CD59 to their deficient erythrocytes. We studied the ability of RBC components prepared from outdated packed RBC collections, as well as high-density lipoprotein (HDL) preparations, rich in CD55 and CD59, to promote protein transfer, as assessed by flow cytometry, immunoblotting, and susceptibility to complement-mediated lysis. By flow cytometry, CD55 and CD59 were present on RBC-derived microvesicles that stained with an antiglycophorin antibody Ab; in addition, soluble CD59 and CD55 were detected by immunoblot in soluble fractions eluated from RBC units stored for more than 35 days, but not in fresh blood. Both commercial HDL preparations and those prepared in our laboratory contained CD55 and CD59, as assayed by immunoblot. When RBC that were deficient (GPI)-anchored protein, obtained from five patients, with PNH were incubated with HDL preparations for 2 to 4 hours, there was significant transfer of both proteins to the cell surface, as demonstrated by flow cytometry. Washed RBC microvesicles, prepared by ultrasonification, also mediated transfer of GPI-linked proteins to deficient RBC. Pretreatment of microvesicles, RBC eluate preparations, and HDL with phosphatidylinositol-specific, phospholipase C, abrogated protein transfer to deficient cells, indicating that increased cell-associated CD55 and CD59 levels were related to insertion of the intact GPI moiety, rather than to simple adhesion. PNH RBC that were exposed to HDL, RBC eluate preparations, or microvesicles demonstrated decreased in vitro complement-mediated hemolysis in the Ham test. Transfer of GPI-linked proteins from soluble preparations containing CD55 and CD59 to PNH erythrocytes is feasible and may have clinical utility.
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PMID:Correction of the PNH defect by GPI-anchored protein transfer. 1074 88

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematologic stem cell disorder classified as an intravascular hemolytic anemia. Abnormal blood cells are deficient in glycosylphosphatidyl inositol (GPI)-anchored proteins. Deficiencies of GPI-anchored complement regulatory proteins, such as decay accelerating factor (DAF) and CD59, render red cells very sensitive to complement and result in complement-mediated hemolysis and hemoglobinuria. In the affected hematopoietic cells from patients with PNH, the first step in biosynthesis of the GPI anchor is defective. Three genes are involved in this reaction step and one of them, an X-linked gene termed PIG-A, is mutated in affected cells. Granulocytes and lymphocytes from the same patient have the same mutation, indicating that a somatic PIG-A mutation occurs in hematopoietic stem cells. The PIG-A gene is mutated in all patients with PNH reported to date. We review these recent advances in the understanding of the molecular pathogenesis of PNH. Furthermore, we present an hypothesis regarding the predominance of the PNH clone, caused by positive selection by hematopoietic suppressive cytokines, such as transforming growth factor (TGF)-beta. In addition, we discuss the possibility of cure for PNH through molecular therapeutic strategy using gene transfer techniques. (Key words: paroxysmal nocturnal hemoglobinuria, glycosylphosphatidylinositol-anchored proteins, PIG-A, clonal dominance, growth advantage, transforming growth factor-beta, gene therapy, molecular therapeutic approach).
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PMID:Paroxysmal nocturnal hemoglobinuria: molecular pathogenesis and molecular therapeutic approaches. 984 22

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired haematological disorder characterized by complement-mediated haemolytic anaemia caused by deficiency of glycosylphosphatidylinositol (GPI) anchored proteins. Somatic mutation of an X-linked gene, PIG-A, is responsible for the defect in biosynthesis of GPI-anchor. It appears that frequency of PNH differs geographically, and seems to be more frequent in some Asian countries, such as Thailand and China. We studied a group of 34 Thai patients with PNH to see whether the somatic mutations in PIG-A, extent of deficiency of GPI-anchored proteins (complete or partial) and complication with aplastic anaemia among Thai patients are different from those in other regions. We determined 37 PIG-A mutations in 33 patients (10 base substitutions, 14 single-base deletions, five multiple-base deletions, three single-base insertions, two multiple base insertions and three others) which were found to be similar to those found in European, American and Japanese patients. Most patients had cells with a complete deficiency of CD59 (type III cells), whereas 19% and 33% of the patients with reliable data for CD59 expression had partially deficient granulocytes and erythrocytes (type II cells), respectively. Most mutations resulted in a complete loss of function of PIG-A in accordance with the prevalent PNH III phenotype. 19 patients (51%) had aplastic anaemia; their PIG-A mutations were not different from those without pre-existing aplastic anaemia. These characteristics of Thai patients are similar to patients from other regions. There was some negative correlation between mean basal Hb concentration and percentage of CD59-negative granulocytes (r = -0. 374; P = 0.0476). In addition, patients with severe anaemia (basal Hb <7 g/dl) had a significantly higher percentage of affected granulocytes than those with mild anaemia (88.5 +/- 9.4 v 64.9 +/- 25.9; P = 0.01). The data suggest that the severity of anaemia in PNH depends partly on the size of the PNH clone.
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PMID:Genotypic, immunophenotypic and clinical features of Thai patients with paroxysmal nocturnal haemoglobinuria. 1023 27


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