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)

In a 2-yr old girl a hemolytic anemia was present since birth requiring multiple blood transfusions. Pyruvate kinase deficiency was suspected on the basis of a marginal enzyme activity, but could not be established due to the presence of massive numbers of donor cells in her peripheral blood. However, by density fractionation we succeeded in the isolation of a small fraction of the patient's own cells, in which a severe pyruvate kinase deficiency could be detected. In contrast hexokinase and glucose-6-phosphate dehydrogenase activities were extremely high, which is indicative that a very immature cell population is present in this fraction. In immunofluorescence studies a clear crossreaction was apparent with anti M2-type pyruvate kinase antibodies, whereas only a faint reaction with anti L-type could be detected. Despite the presence of a slight amount of L-type immunoreactive material, the residual activity in the patient's cell fraction could only be attributed to M2-type pyruvate kinase as was shown by cellulose acetate electrophoresis.
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PMID:Diagnosis of pyruvate kinase deficiency in a transfusion-dependent patient with severe hemolytic anemia. 222 Jul 62

We report the characterization at the molecular level of a mutant glucose-6-phosphate dehydrogenase (G6PD) gene in a Greek boy who presented with a chronic non-spherocytic haemolytic anaemia. In order to identify the mutation from a small amount of patient material, we adopted an approach which by-passes the need to construct a library by using the polymerase chain reaction. The entire coding region was amplified in eight sections, with genomic DNA as template. The DNA fragments were then cloned in an M13 vector and sequenced. The only difference from the sequence of normal G6PD was a T----G substitution at nucleotide position 648 in exon 7, which predicts a substitution of leucine for phenylalanine at amino acid position 216. This mutation creates a new recognition site for the restriction nuclease BalI. We confirmed the presence of the mutation in the DNA of the patient's mother, who was found to be heterozygous for the new BalI site. This is the first transversion among the point mutations thus far reported in the human G6PD gene.
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PMID:Identification of a single base change in a new human mutant glucose-6-phosphate dehydrogenase gene by polymerase-chain-reaction amplification of the entire coding region from genomic DNA. 222 8

Human erythrocyte glucose-6-phosphate dehydrogenase is normally quite stable in the presence of 10 microM NADP+. Certain glucose-6-phosphate dehydrogenase variants lose virtually all their activity at this concentration of NADP+ but are reactivated by 200 microM NADP+. Such variants presumably have a defect in their NADP+-binding site. We analyzed the sequence of cDNA or genomic DNA from seven unrelated patients with hemolytic anemia due to the inheritance of variants that are reactivated by NADP+. Six patients had substitutions of one of three adjacent amino acids, and the seventh patient had another amino acid substitution 23 residues downstream. These amino acids are highly conserved, all being present in rat and all but one being found also in Drosophila. The anomalous electrophoretic behavior of some of the variants can be explained by their loss of ability to bind NADP+. We conclude that the region in which these mutations occur defines the binding domain for NADP+ and that binding NADP+ that has been designated as "structural" and as "catalytic" probably occurs at the same site.
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PMID:Identification of the binding domain for NADP+ of human glucose-6-phosphate dehydrogenase by sequence analysis of mutants. 260 58

Bone marrow and peripheral blood cells may be adversely affected by drugs. Although the risk from most drugs is very small, many cases are reported because of the millions of doses of drugs taken each year by the population. Neutropenia, thrombocytopenia, hemolytic anemia, aplastic anemia, and macrocytic anemia are the commonest effects, in that order. Aplastic anemia is rare, but very serious when it does occur. Adverse effects may be produced by a direct toxic action of the drug or its metabolites on the bone marrow or, less often, on circulating cells. Antineoplastic drugs and chloramphenicol are examples. Most drugs produce their adverse effects through an immunological mechanism. The drug may act as a hapten or may affect the immune system leading to the production of antidrug antibodies and sometimes autoantibodies. Hemolytic anemia may result. Penicillins may behave in this manner. Some drugs act on erythrocytes with enzyme defects, e.g. glucose-6-phosphate dehydrogenase (G-6-PD) abnormalities, to produce hemolysis. In many cases, the mechanism underlying the adverse effect is unknown. The paper lists the drugs reported to have caused some hematological adverse effect and describes the mechanisms in those cases where they are known.
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PMID:Hematologic side effects of drugs. 266 27

Since the discovery of glucose-6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase deficiency, erythroenzymopathies associated with hereditary hemolytic anemia have been extensively investigated. Kinetic and electrophoretic studies have shown that most erythroenzymopathies are caused by the production of a mutant enzyme. Single amino acid substitutions have been determined in G6PD and phosphoglycerate kinase variants by studies of the enzyme. Except for these two enzymes, it has been difficult to purify and to characterize the patient's enzyme because of the low protein contents in red blood cells. Recent advance in recombinant DNA technology has made possible the isolation of normal genomic DNA or cDNA for several enzymes. These results permit us to study the molecular basis of erythroenzymopathies at the nucleotide level. Single base substitutions have been identified in aldolase, triosephosphate isomerase, G6PD and adenylate kinase variants by the cloning and nucleotide sequence of the patients' genes. To date, all of the enzyme-deficient variants which have been investigated are caused by point mutations. An exception is a hemolytic anemia secondary to increased adenosine deaminase (ADA) activity. Red cell ADA activity increases on the order of a hundred-fold in affected individuals. The basic abnormality appears to result from overproduction of structurally normal enzyme due to abnormal translational efficiency.
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PMID:[Pathophysiology and laboratory tests of hemolytic anemia: with special reference to erythroenzymopathies]. 269 73

A case-control study was conducted to test the hypothesis whether the genetic condition of glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with a reduced risk of cancer. One hundred and eighty seven male cancer patients admitted to hospitals in Cagliari (Sardinia, Italy), between November 1984 and March 1986, were compared with 186 male patients with other diseases, except hemolytic anemia, admitted to the same hospitals in the same period. In contrast to previous reports, our study found no reduction of cancer risk in G6PD-deficient subjects. The study had sufficient statistical power to detect a 0.5-fold decrease in the risk of cancer. The recent suggestion from other studies that tumoral cells of G6PD-deficient subjects can produce their own G6PD, seems to be consistent with this negative finding. Among those subjects presenting some level of erythrocyte G6PD activity, the average enzyme activity was significantly higher in cancer patients than in controls. This finding is consistent with previous experimental studies suggesting a positive correlation between cell proliferation and G6PD activity.
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PMID:Glucose-6-phosphate dehydrogenase deficiency and cancer in a Sardinian male population: a case-control study. 270 39

Heinz body hemolytic anemia developed in six full-term infants while at home during the first 2 weeks of life. The disorder first manifested as hyperbilirubinemia. However, in all cases, severe anemia (hemoglobin concentration 49-73 g/L) developed during the 4-12 days of hospitalization. The infants had not been exposed to known oxidants, and their erythrocytes were not glucose-6-phosphate dehydrogenase (G6PD) deficient and contained no unstable hemoglobin. It is hypothesized that in these newborn infants, Heinz body hemolytic anemia developed as a result of ingestion of an oxidant contained in feedings. The nature of this agent is as yet unknown.
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PMID:Idiopathic Heinz body hemolytic anemia in newborn infants. 271 39

Fatal hemolytic anemia occurred in a 71-year-old man after trimethoprim-sulfamethoxazole was given for presumed cystitis. Administration of this combination has previously caused multiple hematologic reactions by affecting folic acid metabolism. Megaloblastic anemia and neutropenia have been produced by both of these agents, while sulfamethoxazole alone has induced acute hemolytic anemia in patients with hereditary deficiency of glucose-6-phosphate dehydrogenase. Although hematologic complications of trimethoprim-sulfamethoxazole treatment usually follow long-term or high-dose therapy, acute reactions apparently may occur at lower doses as well.
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PMID:Death from drug-induced hemolytic anemia. 271 9

Recent work in this laboratory indicated that 2-butoxyethanol (BE) causes acute hemolytic anemia in rats, and activation of BE to butoxyacetic acid (BAA), presumably through the intermediate 2-butoxyacetaldehyde (BAL), is a prerequisite for development of hematotoxicity. In the present studies, the effects of BE and its metabolites, BAL and BAA, on erythrocytes from rats and humans were investigated in vitro. Incubation of BE (up to 10 mM) with blood from male F344 rats caused no hemolysis and resulted in no metabolic alteration of BE. Further, addition of alcohol and aldehyde dehydrogenases, with their co-factors, to the incubation mixture failed to alter BE or its effect. At 20 mM, BE caused significant (P less than or equal to 0.05) hemolysis of rat erythrocytes accompanied by a significant (P less than or equal to 0.05) decrease in hematocrit (HCT). In contrast, incubation of BAL or BAA with rat blood caused time- and concentration-dependent swelling of red blood cells followed by hemolysis; however, BAA was significantly more efficacious than BAL. Addition of aldehyde dehydrogenase and its co-factors significantly (P less than or equal to 0.05) potentiated the effect of BAL on rat erythrocytes. Further in vitro investigation of the cellular mechanisms involved in the hemolytic effect revealed that incubation of rat blood with BAA or BAL caused a time- and concentration-dependent decrease in blood ATP concentration. As observed with the hemolytic effects, the decrease in blood ATP was significantly (P less than or equal to 0.05) greater with BAA than with BAl and was not induced by BE. Further, BAA caused no significant changes in the concentration of reduced glutathione and glucose-6-phosphate dehydrogenase in rat erythrocytes. Assessment of human sensitivity by incubation of human blood with BAA showed minimal swelling or hemolysis of erythrocytes with minimal decline in blood ATP levels at BAA concentrations several-fold higher than required to cause complete hemolysis of rat erythrocytes. In summary, the current studies confirm that the hemolytic effect of BE can be attributed primarily to its metabolite BAA, that hemolysis of rat erythrocytes by BAA or BAL is preceded by swelling and ATP depletion, suggesting that the erythrocyte membrane is the most likely target, and, finally, that human erythrocytes are comparatively insensitive to the hemolytic effects of BAA in vitro.
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PMID:Metabolic and cellular basis of 2-butoxyethanol-induced hemolytic anemia in rats and assessment of human risk in vitro. 273 Jun 82

The interaction of certain metabolites of the 8-aminoquinoline antimalarial primaquine with both normal and glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes and with haemoglobin preparations was studied in an attempt to elucidate the mechanisms of methaemoglobin formation and haemolytic anaemia associated with the use of primaquine. Studies using erythrocytes revealed that oxidation of haemoglobin and reduced glutathione (GSH) was due to the metabolites rather than the parent drug. Incubation of free haemoglobin with 5-hydroxylated metabolites of primaquine also led to oxidation of oxyhaemoglobin and GSH. Oxidation of GSH also occurred in the absence of oxyhaemoglobin. The results suggest a dual mechanism for these oxidative effects, involving autoxidation of the 5-hydroxy-8-aminoquinolines and their coupled oxidation with oxyhaemoglobin. The initial products of these processes would be drug metabolite free radicals, superoxide radical anions, hydrogen peroxide and methaemoglobin. Further free radical reactions would lead to oxidation of GSH, more haemoglobin and probably other cellular constituents. NADPH had no effect on the oxidative effects of the primaquine metabolites in these experiments. In the G6PD-deficient erythrocyte, the oxidation of haemoglobin and GSH leads to Heinz body formation and eventually to haemolysis, the mechanisms of which are as yet unclear. The possible role of oxygen free radicals in the mode of action of 8-aminoquinolines against the malaria parasite is also briefly discussed.
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PMID:Studies on the mechanisms of oxidation in the erythrocyte by metabolites of primaquine. 283 99


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