losartan-potassium and Purpura--Thrombocytopenic

Recombinant cytokines were used to investigate the pathophysiology of Diamond-Blackfan anemia (DBA) and to treat patients with Fanconi's anemia (FA) and amegakaryocytic thrombocytopenic purpura (AMT). We compared the erythroid burst forming units (BFU-E) colony growth of six DBA patients with four normal controls. BFU-E showed erythropoietin (Epo) dose dependence in all patients, although colony numbers were reduced in comparison with normals. The number and size of BFU-E were increased with the addition to Epo of interleukin 3 (IL-3) or Steel factor (SF), but IL-3 + SF was not synergistic. SF increased the nonadherent cell production in DBA long-term bone marrow cultures, and stromal cells from DBA patients showed normal SF mRNA transcripts. These data suggest that SF is not involved in the pathogenesis of DBA, although it may be useful in treatment. A small group of patients with FA and bone marrow failure were treated with daily s.c. granulocyte-macrophage colony stimulating factor (GM-CSF). Toxicity was minimal, and the majority of the patients responded with significant, sustained increase in neutrophils. Multilineage response was rare. GM-CSF may thus be palliative in patients with FA. Five patients with AMT were treated with IL-3 or IL-3 followed by GM-CSF in a phase I/II study. There was minimal toxicity, and IL-3, but not GM-CSF, resulted in improved platelet counts in two patients and decreased platelet transfusion requirements in the other three. Prolonged IL-3 treatment resulted in platelet increases in two of the latter patients. Thus, IL-3 may contribute to the treatment of patients with AMT.

Topics: Adult; Bone Marrow; Cells, Cultured; Child, Preschool; Drug Synergism; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Fanconi Anemia; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Immunologic Factors; Infant; Interleukin-3; Leukocyte Count; Platelet Count; Purpura, Thrombocytopenic; Recombinant Proteins; Stem Cell Factor; Treatment Outcome

The present study was designed to test the concept that platelets release a humoral factor that plays a regulatory role in megakaryopoiesis. The results showed that, among various hematoregulatory cytokines examined, transforming growth factor-beta1 (TGF-beta1) was by far the most potent enhancer of mRNA expression of bone marrow stromal thrombopoietin (TPO), a commitment of lineage specificity. The TPO, in turn, induced TGF-beta receptors I and II on megakaryoblasts at the midmegakaryopoietic stage; at this stage, TGF-beta1 was able to arrest the maturation of megakaryocyte colony-forming units (CFU-Meg). This effect was relatively specific when compared with its effect on burst-forming unit-erythroid (BFU-E) or colony-forming unit-granulocyte-macrophage (CFU-GM). In patients with idiopathic thrombocytopenic purpura (ITP), the levels of both TGF-beta1 and stromal TPO mRNA were correlatively increased and an arrest of megakaryocyte maturation was observed. These in vivo findings are in accord with the aforementioned in vitro results. Thus, the results of the present investigation suggest that TGF-beta1 is one of the pathophysiological feedback regulators of megakaryopoiesis.

Topics: Bone Marrow; Colony-Forming Units Assay; Erythropoietin; Gene Expression Regulation; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Humans; Interleukin-3; Interleukin-6; Megakaryocytes; Models, Biological; Purpura, Thrombocytopenic; Recombinant Proteins; Reference Values; RNA, Messenger; Stromal Cells; Thrombopoietin; Transcription, Genetic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: Animals; Biological Assay; Blood Platelets; Erythropoietin; Glycoproteins; Hematopoiesis; Humans; Megakaryocytes; Mice; Purpura, Thrombocytopenic; Thrombopoietin

Using procedures that were effective in the purification of human urinary erythropoietin (Epo), we attempted initial purification of megakaryocyte colony-stimulating factors (CSF) in urinary extracts from patients with aplastic anemia (AA) and idiopathic thrombocytopenic purpura (ITP). Comparison of colony stimulation by purified human Epo and crude urinary extracts revealed: (1) that the pure Epo augments megakaryocyte colony formation in culture and (2) MEG-CSF activity is also present in materials other than Epo in the crude urinary extracts from the two types of patients. Similar to purification of Epo, ethanol precipitation and sulfopropyl-Sephadex chromatography provided twofold and threefold increases in the specific activity of MEG-CSF, respectively. In contrast to Epo, however, significant inactivation of MEG-CSF activity was seen with phenol treatment. The elution profile of MEG-CSF seen on hydroxylapatite chromatography of urinary extracts was different from that of Epo. These data provided a basis for initial steps for purification of MEG-CSF and support the notion that MEG-CSF is distinct from Epo.

Topics: Aminosalicylic Acids; Anemia, Aplastic; Cells, Cultured; Chromatography; Colony-Stimulating Factors; Erythropoietin; Ethanol; Humans; Hydroxyapatites; Megakaryocytes; Purpura, Thrombocytopenic

The influence of splenectomy on erythroid burst colony formation by peripheral blood mononuclear cells from 10 patients (four with hereditary spherocytosis, two with beta-thalassaemia major, two with Hodgkin's disease and two with idiopathic thrombocytopenic purpura) was studied. In every instance splenectomy was followed by a lowering of blood BFU-E. The post-splenectomy levels ranged from 0 to 30% of the preoperative levels. Mononuclear cells from the spleens of eight patients were cultured and found to contain numerous BFU-E. The total quantity of BFU-E in the whole blood and in the spleen of the patients was generally of the same order of magnitude. The number of splenic BFU-E did not correlate with spleen size. Splenic BFU-E differed from peripheral blood BFU-E in that they were more sensitive to erythropoietin (Ep) and in that they failed to respond to burst promoting activity (BPA) produced by preincubating the spleen mononuclear cells with phytohaemagglutinin M (PHA). In contrast, media conditioned by PHA-treated spleen cells contained BPA active on peripheral blood BFU-E from normal individuals. These data suggest that the spleen may have an influence on the numbers and functional properties of BFU-E.

Topics: Adolescent; Adult; Anemia, Hemolytic; Child; Child, Preschool; Erythrocyte Count; Erythrocytes; Erythropoietin; Female; Hematopoietic Stem Cells; Hodgkin Disease; Humans; Male; Phytohemagglutinins; Purpura, Thrombocytopenic; Spleen; Splenectomy

Topics: Adult; Animals; Antibodies; Antibodies, Antinuclear; Autoimmune Diseases; Binding Sites; Bone Marrow Examination; Erythropoiesis; Erythropoietin; Female; Hematocrit; Heme; Hemoglobinometry; Humans; Immune Sera; Immunoglobulin G; In Vitro Techniques; Iron Isotopes; Leukocyte Count; Mice; Myasthenia Gravis; Purpura, Thrombocytopenic; Rats; Reticulocytes; Rheumatoid Factor

Topics: Adult; Anemia, Hypochromic; Animals; Biological Assay; Blood Cell Count; Blood Platelets; Child; Erythropoietin; Humans; Iron Isotopes; Male; Purpura, Thrombocytopenic; Rats; Thrombopoietin