losartan-potassium and Hemoglobinuria--Paroxysmal

Three patients with paroxysmal nocturnal hemoglobinuria (PNH) and severe anemia were treated with high-dose recombinant human erythropoietin (rHEpo) and low-dose corticosteroids. During therapy their hemoglobin levels gradually improved and no blood transfusions were required. Neither rHEpo nor corticosteroids caused any side effects. This study shows that high rHEpo and low corticosteroid doses may improve the anemia of PNH patients.

Topics: Acute Disease; Adolescent; Adult; Anemia; Drug Therapy, Combination; Erythropoietin; Female; Hemoglobinuria, Paroxysmal; Humans; Male; Prednisolone; Recombinant Proteins; Remission Induction

We reviewed clinical and molecular data of 23 consecutive unrelated patients affected by paroxysmal nocturnal hemoglobinuria (PNH) (19 with hemolytic PNH, 3 with aplastic anemia/PNH, and 1 with myelodysplasia/PNH syndrome) with a mean follow-up of 11.8 years. Five patients had thrombotic episodes, and 10 needed regular blood transfusions; 2 died for cerebral hemorrhage and kidney failure, and 2 spontaneously recovered from PNH. Twenty different PIG-A gene mutations were detected in 21/23 patients: 15 frameshift, 1 splicing, 2 nonsense, and 2 missense mutations. Two mutations (DelG341 and IVS2 +1g-a) were detected twice. A PIG-A mutated clone was also revealed in the two patients in complete clinical remission. One patient with aplastic anemia/PNH syndrome was treated with two courses of antilymphocyte globulin and cyclosporin with partial sustained response. Six patients were given rHu-EPO 150 U/kg/day s.c. for at least 6 months: one became transfusion-independent for 8 months and then discontinued treatment for clinical complications; one displayed a mean rise of Hb of 1.5 g/dL and is currently maintaining Hb levels higher than 9 g/dL after 54 months of therapy. Mutation specific quantitative-competitive PCR showed that the rise of hemoglobin was related to an increase of PIG-A negative molecules, suggesting that the efficacy of rHu-EPO therapy may be due to the stimulation of the abnormal clone.

Topics: Adolescent; Adult; Antilymphocyte Serum; Cyclosporine; DNA Mutational Analysis; Drug Monitoring; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Hemoglobinuria, Paroxysmal; Humans; Immunosuppression Therapy; Male; Membrane Proteins; Middle Aged; Mutation; Polymerase Chain Reaction; Recombinant Proteins; Thrombosis; Treatment Outcome

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Blood Transfusion; Combined Modality Therapy; Erythropoietin; Hematinics; Hemoglobinuria, Paroxysmal; Humans; Iron; Practice Guidelines as Topic; Trace Elements

Topics: Aged; Autoantibodies; Erythropoietin; Hemoglobinuria, Paroxysmal; Humans; Male; Myelodysplastic Syndromes

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis leading to anemia and other clinical manifestations. Transfusions are often required to support hemoglobin at tolerable levels. A PNH patient with aplastic anemia was treated with the complement inhibitor eculizumab, followed by concurrent treatment with recombinant human erythropoietin (rHuEpo). Eculizumab alone reduced hemolysis, increased PNH red blood cell (RBC) mass, and decreased transfusions. Addition of rHuEpo during eculizumab therapy, enhanced erythropoiesis, further increased PNH RBC mass and hemoglobin levels, and rendered the patient transfusion independent for more than two years. These data show that driving erythropoiesis during eculizumab treatment provided further benefit to a patient with PNH and underlying bone marrow failure.

Topics: Anemia, Aplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Blood Transfusion; Complement C5; Drug Synergism; Erythrocyte Indices; Erythropoiesis; Erythropoietin; Hemoglobins; Hemoglobinuria, Paroxysmal; Hemolysis; Humans; Male; Middle Aged; Recombinant Proteins; Treatment Outcome

Paroxysmal nocturnal hemoglobinuria (PNH) results from somatic mutations of the X-linked PIG-A (phosphatidylinositol glycan-class A) gene, which occurs on a hematopoietic stem cell level, leading to a proportion of blood cells being deficient in all glycosylphosphatidylinositol (GPI)-anchored surface proteins. Although these GPI-deficient cells can explain many of the clinical symptoms of PNH, the pathogenesis of PNH is still somewhat obscure and many questions remain. To assess the hematopoietic defect involved in PNH, CD34+ CD59+ (normal phenotype hematopoietic stem/progenitor) and CD34+ CD59- (PNH phenotype) cells from PNH patients (n = 16) and CD34+ CD59+ cells from healthy volunteers (n = 10) were sorted as single cells into 96-well flat-bottom culture plates containing culture medium supplemented with stem cell factor, interleukin (IL)-3, erythropoietin, granulocyte-macrophage-colony-stimulating factor (GM-CSF), G-CSF, IL-6, thrombopoietin, and Flt-3 ligand. We found that the single PNH CD34+ CD59- cells had a growth advantage over the single CD34+ CD59+ cells to some extent, but they both had impaired growth abilities compared with CD34+ cells from healthy volunteers.

Topics: Adolescent; Adult; Antigens, CD34; Bone Marrow; Cell Division; Cell Separation; Cells, Cultured; Colony-Forming Units Assay; Erythropoietin; Female; Flow Cytometry; Glycosylphosphatidylinositols; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Hemoglobinuria, Paroxysmal; Humans; Male; Membrane Proteins; Middle Aged; Recombinant Proteins

Topics: Adult; Anemia, Aplastic; Antilymphocyte Serum; Bone Marrow Transplantation; Erythropoietin; Hemoglobinuria, Paroxysmal; Humans; Male; Myelodysplastic Syndromes; Splenectomy; Transplantation Conditioning

We describe a 28-year-old man with paroxysmal nocturnal haemoglobinuria (PNH) and a high transfusion requirement. Prior to and during therapy with recombinant human erythropoietin (rHuEpo), we evaluated the levels of 'decay-accelerating-factor', CD55, and 'membrane-inhibitor-of-reactive-lysis', CD59, as markers of the disease, whilst CD58, a marker present on leucocytes, was utilized to monitor normal haemopoietic activity. The patient became transfusion independent 1 month after beginning rHuEpo and remains well. The analysis of CD55, CD59 and CD58 suggests that the efficacy of rHuEpo was due to a selective rHuEpo action on normal erythroid clones.

Topics: Adult; CD55 Antigens; CD58 Antigens; CD59 Antigens; Erythrocytes; Erythropoietin; Flow Cytometry; Hemoglobinuria, Paroxysmal; Humans; Male

In patients with paroxysmal nocturnal hemoglobinuria (PNH), we measured plasma concentrations of endogenous hematopoiesis-regulatory cytokines to characterize bone marrow (BM) hypoplasia which is a major cause of death. Contrary to 10 healthy individuals, all 14 patients with PNH showed increases of erythropoietin (Epo) and granulocyte-colony stimulating factor (G-CSF). There were no signs of infection, renal dysfunction or hypoxia. The lower the hemoglobin level and granulocyte count, the higher the plasma Epo and G-CSF levels. In contrast, marked differences were not found in the levels of interleukin-3 (IL-3), tumor necrosis factor-alpha (TNF-alpha), stem cell factor (SCF), granulocyte/macrophage-colony stimulating factor (GM-CSF), or interferon-gamma) (IF-gamma). The cytokine profiles of PNH patients were quite similar to those of patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS). The cytokine profiles may support a pathological relationship between PNH and these stem cell disorders.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hemoglobinuria, Paroxysmal; Humans; Male; Middle Aged

In order to assess the rationale and possible indications for the use of recombinant erythropoietin in paroxysmal nocturnal haemoglobinuria (PNH), we have measured endogenous erythropoietin (Epo) levels in 18 patients with PNH and in 44 patients with iron deficiency anaemia (IDA). In both groups of patients we found a significant inverse correlation between Epo and haemoglobin (Hb). However, the mean Epo level was significantly higher in the PNH group (385 mU/ml) than in the IDA group (136 mU/ml). The range of Epo levels at any given Hb was greater in the PNH group than in the IDA group. There was a significant positive correlation between Epo and absolute reticulocyte count. Since Epo administration is unlikely to benefit patients with high levels of endogenous Epo, we conclude that in the majority of patients with PNH there is no indication for treatment with Epo.

Topics: Erythropoietin; Hemoglobins; Hemoglobinuria, Paroxysmal; Humans; Iron

Topics: Erythropoietin; Hemoglobinuria, Paroxysmal; Humans; Patient Selection; Recombinant Proteins

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.

Topics: Adult; Anemia; Erythropoietin; Hemoglobinuria, Paroxysmal; Humans; Male; Recombinant Proteins

Blood erythropoietin (EPO) concentration was measured by radioimmunoassay in 513 patients with various diseases. Untreated polycythemia vera showed lower EPO concentration than normal. Aplastic anemia (AA) revealed the highest EPO level among all anemic diseases in relation to hematocrit value. EPO level of AA patients who underwent bone marrow transplantation was as low as normal subjects even when the anemia has not fully recovered. Paroxysmal nocturnal hemoglobinuria (PNH) showed unusually high EPO concentration among hemolytic anemias. In normal subjects, blood EPO concentration showed a diurnal rhythm that was higher at night than during the daytime. These findings suggest the diagnostic usefulness of measurement of EPO in blood diseases.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Aplastic; Bone Marrow Transplantation; Circadian Rhythm; Erythropoietin; Female; Hemoglobinuria, Paroxysmal; Humans; Male; Middle Aged; Polycythemia Vera; Radioimmunoassay; Reference Values

In a dose escalation study we tested the feasibility and tolerance of high-dose recombinant human erythropoietin (r-HuEPO) therapy in four patients with ineffective erythropoiesis due to myelodysplastic syndromes (MDS) or paroxysmal nocturnal hemoglobinuria (PNH). Recombinant human EPO was administered i.v. with an initial dose of 50 U/kg body weight (BW) three times per week. The dose was increased by steps of 25 or 50 U/kg bW with intervals of 1-4 weeks up to a maximum dose of 500 U/kg BW three times per week. All patients were treated as outpatients. Pre-study treatment with cyclosporin A and/or Danazol was continued in three patients. In one patient r-HuEPO was discontinued after 20 weeks because of relapse of severe aplastic anemia. No major side effects were observed even at the maximum dose. One patient with PNH showed an increase of hemoglobin from 89 to 139 g/liter that permitted monthly phlebotomies to reduce his iron overload. In one patient with MDS the reticulocyte count increased from 2.5 to 50 x 10(9)/liter, and the transfusion requirement decreased to 2 U every 3-4 weeks instead of every 2 weeks. Two patients did not complete the whole treatment period and showed no rise in reticulocyte count. We conclude that high dose r-HuEPO therapy is feasible in patients with anemia due to MDS or PNH. High-dose r-HuEPO appears to have some effect on anemia due to ineffective erythropoiesis in a subgroup of patients. Further studies are needed to identify potential responders and to define the optimal administration of r-HuEPO.

Topics: Adult; Anemia; Blood Transfusion; Erythrocyte Count; Erythropoietin; Female; Hemoglobins; Hemoglobinuria, Paroxysmal; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Reticulocytes

Topics: Erythropoietin; Female; Hemoglobinuria, Paroxysmal; Humans; Kidney Failure, Chronic; Middle Aged; Patient Care Planning

Topics: Animals; Arylsulfatases; Erythropoiesis; Erythropoietin; Glucuronidase; Hemoglobinuria, Paroxysmal; Humans; Mice; Solubility

Topics: Dithiothreitol; Erythropoietin; Ethylmaleimide; Female; Hemoglobinuria, Paroxysmal; Humans; Male; Molecular Weight; Multiple Myeloma

Topics: Anemia, Aplastic; Anemia, Sideroblastic; Animals; Biological Assay; Circadian Rhythm; Computers; Dialysis; Erythropoietin; Evaluation Studies as Topic; Female; Freeze Drying; Hemagglutination Tests; Hemoglobinuria, Paroxysmal; Humans; Iron Radioisotopes; Male; Methods; Mice; Mice, Inbred Strains; Microchemistry; Oxygen Consumption; Thalassemia; Ultrafiltration

Topics: Acetone; Adrenal Cortex Hormones; Anemia; Animals; Chemical Precipitation; Chromatography, DEAE-Cellulose; Chromatography, Thin Layer; Dialysis; Erythropoiesis; Erythropoietin; Ethanol; Female; Hemoglobinuria, Paroxysmal; Humans; Hydrogen-Ion Concentration; Iron Radioisotopes; Male; Membranes, Artificial; Mice; Molecular Weight; Multiple Myeloma; Solubility; Solvents

Topics: Body Weight; Chromatography, DEAE-Cellulose; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Filtration; Hemoglobinuria, Paroxysmal; Humans; Hydrogen-Ion Concentration; Iron Isotopes; Male; Membranes, Artificial; Methods; Multiple Myeloma; Urine

Topics: Chemistry Techniques, Analytical; Erythropoiesis; Erythropoietin; Filtration; Hemoglobinuria, Paroxysmal; Humans; Hydrogen-Ion Concentration; Male; Molecular Weight; Multiple Myeloma; Protein Binding; Proteins

Topics: Albumins; Anemia; Animals; Binding Sites; Cellulose; Chromatography; Dialysis; Erythropoietin; gamma-Globulins; Hemoglobinuria, Paroxysmal; Humans; Immunoelectrophoresis; Methods; Mice; Multiple Myeloma; Phenols; Rabbits

Topics: Adult; Anemia, Aplastic; Erythropoietin; Female; Fluoxymesterone; Hemoglobinuria, Paroxysmal; Humans; Male; Methods; Middle Aged; Multiple Myeloma; Primary Myelofibrosis; Sex Factors; Time Factors

Topics: Acetylcholinesterase; Alkaline Phosphatase; Anemia; Anemia, Hemolytic; Anticoagulants; Australia; Blood Transfusion; Chromium Isotopes; Coombs Test; Dextrans; Diagnosis, Differential; Drug Therapy; Epoetin Alfa; Erythrocyte Count; Erythrocytes; Erythropoietin; Hematologic Tests; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Hemosiderin; Humans; Iron; Iron Isotopes; Phenindione; Prednisone; Splenectomy; Waldenstrom Macroglobulinemia