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)

The regulation of megakaryocytopoiesis and platelet production has not yet been clearly elucidated. Several cytokines have been shown to be capable of producing megakaryocyte colonies from bone marrow [i.e. Interleukin (IL)-3, granulocyte-macrophage (GM)-colony-stimulating factor (CSF), erythropoietin (Epo)]. In addition, other activities have been reported to stimulate megakaryocyte precursors, yet a megakaryocyte-CSF (Meg-CSF) has not been purified to homogeneity and IL-3, GM-CSF and/or Epo often contaminate purification attempts which could account for the activities. A Meg-CSF has been isolated from the urine of patients with aplastic anaemia and purified by sequential ultrafiltration, cation exchange, G-50 chromatography, preparative PAGE, chromatofocusing and cation exchange HPLC. The activity of this material is 2-4 x 10(4) CFU-Meg/mg as measured in a murine marrow, serum-containing assay. This activity also stimulates CFU-Meg in the absence of adherent accessory cells and in serum-free cultures, indicative of the direct stimulation on CFU-Meg. Immunoassays, colony forming assays, and proliferation assays demonstrate that purified Meg-CSF has no GM-CSF, IL-3, M-CSF, G-CSF or IL-1 alpha, -3, -6, -9 and -11. In confirmation of these results, neutralizing antibody to IL-6 also did not abrogate Meg-CSF activity. Therefore the previously-reported megakaryocyte colony-stimulating activity in purified aplastic anaemia patient urine is due to a unique cytokine: Meg-CSF.
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PMID:Megakaryocyte colony-stimulating factor (Meg-CSF) is a unique cytokine specific for the megakaryocyte lineage. 839 18

To clarify the regulatory mechanism of thrombopoietin (TPO, c-Mpl ligand) in chronic thrombocytopenic conditions, we determined TPO levels in the sera of patients with aplastic anaemia (AA; n = 26) and idiopathic thrombocytopenic purpura (ITP; n = 32) by an enzyme-linked immunosorbent assay. Despite a similarity in platelet counts, serum TPO levels in the AA group were markedly higher than those in the ITP group: 20.41 +/- 9.71 f mol/ml (mean +/- SD) and 1.66 +/- 0.55 f mol/ml, respectively, both of which were significantly elevated compared to normal subjects (n = 41; 1.22 +/- 0.37). In both groups, serum TPO level showed an inverse correlation with the platelet count. We determined the megakaryocyte volume using bone marrow clot section and found that it was markedly small in the AA group; while in the ITP group it was augmented with a correlation to serum TPO level. Our findings suggest that TPO levels may be regulated not only by platelets but also megakaryocytes in AA and ITP.
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PMID:Regulation of serum thrombopoietin levels by platelets and megakaryocytes in patients with aplastic anaemia and idiopathic thrombocytopenic purpura. 886 22

The effects of native thrombospondin (TSP), an 18 kd recombinant protein comprising residues 1-174 of TSP (TSP1-174) with heparin-binding domain and a fusion protein comprising residues 559-669 of TSP (TSP559-669) on murine hematopoiesis, were studied by using different in vitro culture systems. TSP by itself did not show an inhibitory effect on colony-forming unit-megakaryocyte (CFU-MK) growth in a serum-free agar system and on the growth of colony-forming unit-granulocyte and macrophage (CFU-GM) in a plasma clot system. It was, however, found that in the plasma clot culture system when using aplastic anemia serum as the source of thrombopoietin or C-Mpl ligand (TPO), TSP and TSP1-174, but not TSP559-669, were able to inhibit the growth of CFU-MK from unfractionated and lineage negative (Lin-) bone marrow cells in a dose-dependent manner. A statistically significant suppression was seen at 1 microg/ml of TSP and 5 microg/ml of TSP1-174. This inhibitory effect of TSP was further found in both the serum-free agar system and the plasma clot system without aplastic anemia serum, where megakaryocyte colony growth was stimulated by recombinant TPO, basic fibroblast growth factor (bFGF), or interleukin-3 (IL-3). In a methylcellulose system, where a combination of stem cell factor (SCF), IL-3, and granulocyte/macrophage colony-stimulating factor (GM-CSF) were used, TSP inhibited the growth of colony-forming unit-granulocyte-erythroblast, megakaryocyte, and macrophage (CFU-GEMM) but not CFU-GM and burst-forming unit-erythroblast (BFU-E). Interestingly, this inhibitory effect of TSP on megakaryocyte colony growth could be counteracted by Fraxiparin, a low-molecular-weight heparin. These results demonstrate that TSP is a negative modulator of megakaryocytopoiesis and suggest that its inhibitory effect is at least partially mediated by N-terminal heparin-binding domain.
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PMID:Thrombospondin, a negative modulator of megakaryocytopoiesis. 901 60

The serum levels of thrombopoietin (TPO) were measured in 16 patients with thrombotic thrombocytopenic purpura (TTP), 12 with hemolytic uremic syndrome (HUS), 10 with aplastic anemia (AA), 10 with disseminated intravascular coagulation (DIC), and 71 with idiopathic thrombocytopenic purpura (ITP). The serum TPO levels were measured with a sensitive sandwich enzyme-linked immunosorbent assay. The serum TPO level in the ITP group (1.68 +/- 0.85 fmol/ml) were not significantly increased compared with those of the normal subjects. The TPO levels in the TTP (2.77 +/- 1.38 fmol/ml) and HUS groups (5.77 +/- 4.41 fmol/ml) were higher than those of the normal subjects. The patients with AA (12.7 +/- 8.0 fmol/ml) and those with DIC (13.3 +/- 5.7 mol/ml) had significantly higher serum TPO levels than did the normal subjects and ITP patients. The TPO levels were well correlated with the platelet counts in the TTP patients, and were negatively correlated with the platelet counts in the ITP patients. These results suggest that the serum TPO levels in some thrombocytopenic diseases are regulated not only by the platelet count and the megakaryocyte mass, but also by other factors.
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PMID:Increased serum levels of thrombopoietin in patients with thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, or disseminated intravascular coagulation. 935 24

Agnogenic myeloid metaplasia (AMM) is a disease characterized by bone marrow megakaryocyte hyperplasia and clusters of megakaryocytes, in which many of the megakaryocytes are atypical. In order to elucidate the mechanisms of megakaryocytosis, ELISA assays of blood levels of thrombopoietin (TPO), interleukin-6 (IL-6) and interleukin-11 (IL-11) were done in 45 patients with AMM and compared with normal volunteer controls. Higher blood TPO levels were found in AMM than in controls (P < 0.0001), and blood TPO levels were correlated with the degree of marrow fibrosis (P = 0.0078). Blood levels of IL-6 were also significantly higher in AMM, when compared with controls (P < 0.0001). However, no correlation was found between blood IL-6 levels and degree of marrow fibrosis. No correlation was found between either TPO or IL-6 and the number of blood platelet counts, the number of marrow megakaryocytes, WBC counts, or the degree of splenomegaly. Blood IL-11 levels were undetectable in most patients and no significant difference was found in AMM as compared to controls. The present study demonstrated that, while in idiopathic thrombocytopenic purpura (ITP) or aplastic anemia, blood TPO levels are relatively correlated with the numbers of platelet and/or megakaryocyte mass, blood TPO levels do not correlate with blood platelet counts, or marrow megakaryocyte mass in AMM. Therefore, in AMM, other mechanisms such as the number of TPO receptors on platelets or megakaryocytes, c-MPL receptor abnormalities, abnormal production of TPO mRNA and so on, will have to be studied. Furthermore, TPO may play a significant role in the pathogenesis of marrow fibrosis; IL-6 may be a factor in the development of marrow megakaryocytosis but its elevated blood levels may represent a secondary immune phenomenon; and IL-11 probably does not play a significant role in causing marrow megakaryocytosis in this disease.
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PMID:Blood thrombopoietin, IL-6 and IL-11 levels in patients with agnogenic myeloid metaplasia. 936 14

We investigated the hematopoietic reservoir in 43 severe aplastic anemia (SAA) patients following immunosuppression (IS) (n = 15) or bone marrow transplantation (BMT) (n = 28), at a median interval of 5 years (range, 2-20) from treatment. All patients had normal blood counts, good marrow cellularity, and normal numbers of colony forming unit-granulocyte macrophages (CFU-GM). Burst forming unit-erythroid (BFU-E) and colony forming unit-granulocyte erythroid megakaryocyte macrophages (CFU-GEMM) numbers were reduced when compared with normal controls. However, the most pronounced defect was observed at the level of long-term culture-initiating cells (LTC-IC), which significantly differed from controls (P < .00001) both for IS and BMT patients. Their number did not improve with time and was not affected by transplant or treatment-related variables. When IS patients were compared with BMT we found comparable numbers of CFU-GEMM (P = .8) and LTC-IC (P = .9), but lower numbers of BFU-E and CFU-GM (P = .05 and P = .004, respectively), suggestive of a persistent suppressive mechanism. These data indicate that LTC-IC numbers are severely reduced in BMT and IS patients, contradicting the common belief that the former are fully reconstituted as compared with the latter. In addition, the number of mature cells and committed progenitors does not seem to reflect the real size of the hematopoietic reservoir and few stem cells may be sufficient to guarantee normal hematopoiesis long term.
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PMID:The assessment of the hematopoietic reservoir after immunosuppressive therapy or bone marrow transplantation in severe aplastic anemia. 949 Jun 78

To evaluate the diagnostic value of thrombopoietin (TPO, c-mpl ligand) measurements, and clarify the regulatory mechanisms of TPO in normal and in thrombocytopenic conditions, the plasma TPO concentration was determined in normal individuals (n = 20), umbilical cord blood (n = 40), chronic idiopathic thrombocytopenic purpura (ITP; n = 16), in severe aplastic anaemia (SAA; n = 3), chemotherapy-induced bone marrow hypoplasia (n = 10), myelodysplastic syndrome (MDS; n = 11), and sequentially during peripheral blood progenitor cell transplantation (n = 7). A commercially available ELISA and EDTA-plasma samples were used for the analysis. The plasma TPO concentration in the normals and umbilical cord blood were 52 +/- 12 pg/ml and 66 +/- 12 pg/ml, respectively. The corresponding values in patients with SAA and chemotherapy-induced bone marrow hypoplasia were 1514 +/- 336 pg/ml and 1950 +/- 1684 pg/ml, respectively, and the TPO concentration, measured sequentially after myeloablative chemotherapy and peripheral blood progenitor cell transplantation, was inversely related to the platelet count. In contrast, the plasma TPO recorded in patients with ITP (64 +/- 20 pg/ml) and MDS (68 +/- 23 pg/ml) were only slightly higher than normal levels. In conclusion, TPO levels were significantly elevated in patients in which bone marrow megakaryocytes and platelets in circulation were markedly reduced, whereas TPO levels were normal in ITP patients, and only slightly increased in the MDS patients. These latter patients displayed a preserved number of megakaryocytes in bone marrow biopsies. Our data support the suggestion that megakaryocyte mass affects the plasma TPO concentration. In thrombocytopenic patients a substantially increased plasma TPO implies deficient megakaryocyte numbers. However, TPO measurements do not distinguish between ITP and thrombocytopenia due to dysmegakaryopoiesis, as seen in MDS patients.
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PMID:Plasma thrombopoietin levels in thrombocytopenic states: implication for a regulatory role of bone marrow megakaryocytes. 963 81

The function of bone marrow (BM) stromal thrombopoietin (TPO) in megakaryopoiesis remains unknown. In the present study we attempted to clarify the pathophysiological implications of stromal TPO in normal subjects (NS) and in patients with idiopathic thrombocytopenic purpura (ITP), aplastic anemia (AA), and essential thrombocythemia (ET) by measuring TPO concentrations in BM and peripheral blood (PB) and by estimating the levels of stromal TPO mRNA with TaqMan fluorescence-based post-reverse transcription-polymerase chain reaction product detection system. The results showed that TPO concentrations in PB were significantly elevated in patients with ITP (34.9 +/- 11.7 pg/mL) and AA (364.1 +/- 153.5 pg/mL) but within normal range in patients with ET (each 20.0 and 22.1; NS, 22.1 +/- 8.2 pg/mL). In all subjects, the TPO concentrations in BM correlated well with the PB levels, and the former were consistently higher than the latter. The concentrations of TPO in BM also correlated with the levels of TPO mRNA in stromal cells. Furthermore, expression levels of TPO mRNA clearly correlated with megakaryocyte counts in NS and patients with ITP, indicating that stromal TPO actually enhances megakaryopoiesis. Thus, our results in the present study indicate that TPO from BM stromal cells is considered to play an essential role for megakaryopoiesis under various patho-physiological conditions.
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PMID:Concentrations of thrombopoietin in bone marrow in normal subjects and in patients with idiopathic thrombocytopenic purpura, aplastic anemia, and essential thrombocythemia correlate with its mRNA expression of bone marrow stromal cells. 963 98

We report a case of secondary myelodysplastic syndrome (MDS) with monosomy 7, which evolved from severe aplastic anemia (SAA) after long-term use of granulocyte colony-stimulating factor (G-CSF). A 36 year old female was admitted for detailed examination and treatment of pancytopenia. SAA was diagnosed based on hypoplastic bone marrow and a normal chromosome study. She was treated with anti-thymocyte globulin (ATG), ciclosporin A (CsA) and G-CSF, which resulted in gradual improvement of not only the myeloid but also the erythroid-megakaryocyte series. However, bone marrow dysplasia with monosomy 7 was observed after 7 months of a combination therapy of immunosuppressant and G-CSF, which prompted the discontinuation of G-CSF administration. Thereafter, bone marrow hypoplasia gradually progressed, resulting in a second aplastic crisis. During this process, the proportion of marrow cells showing monosomy 7 decreased, and the proportion with normal karyotype increased. Re-administration of G-CSF induced a trilineage, though dysplastic, hematological response; but the monosomy 7 positive population increased again. These observations indicated the presence of G-CSF dependent hematopoiesis associated with monosomy 7 in this patient. Although many G-CSF related MDS/AML cases with this leukemia-specific abnormal karyotype have been reported with emphasis on the harmful effects of G-CSF, G-CSF was useful even after the appearance of monosomy 7 as a means of avoiding life-threatening infection in this patient.
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PMID:Granulocyte colony-stimulating factor (G-CSF) dependent hematopoiesis with monosomy 7 in a patient with severe aplastic anemia after ATG/CsA/G-CSF combined therapy. 980 78

Recombinant human megakaryocyte growth and development factor (rHuMGDF), a truncated form of the Mpl ligand, stimulates megakaryopoiesis both in vitro and in vivo. We describe the in vitro effect of pegylated recombinant human MGDF (PEGrHuMGDF) alone and in combination with other haemopoietic growth factors (G-CSF, GM-CSF, IL3, IL6, erythropoietin, SCF) on megakaryopoiesis in bone marrow from 11 normal subjects and 19 patients with aplastic anaemia (AA). We used semi-solid cultures to assess megakaryocyte colony growth (CFU-Mk) and 7 d suspension cultures to assess production of platelet glycoprotein IIIa (CD61) positive cells. CFU-Mk growth from normal marrow increased 3-4-fold and CD61+ve cells in suspension culture increased 8-10-fold with the addition of 10 ng/ml PEGrHuMGDF. In normal subjects growth factor combinations further increased responses in suspension culture, PEGrHuMGDF + SCF, PEGrHuMGDF + IL3 and PEGrHuMGDF + SCF + IL3 + Epo (P<0.05). IL6, GM-CSF, G-CSF or Epo added with PEGrHuMGDF did not consistently give this increase. CFU-M. growth from AA marrow remained very low in the presence of PEGrHuMGDF, with or without the addition of other growth factors. CD61+ve cells in suspension culture were, however, increased in the presence of PEGrHuMGDF alone in 12/19 AA cases. Of the 12 patients responsive to PEGrHuMGDF, nine were tested with additional growth factors and further responses were seen in six. In the AA cases PEGrHuMGDF+SCP and PEGrHuMGDF+SCF+IL3+Epo gave the highest responses. These data suggest that PEGrHuMGDF, alone or in combination with SCF and/or IL3, can enhance megakaryocyte proliferation in some patients with aplastic anaemia and may therefore have a role in the treatment of thrombocytopenia in these cases.
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PMID:The in vitro effect of pegylated recombinant human megakaryocyte growth and development factor (PEGrHuMGDF) on megakaryopoiesis in patients with aplastic anaemia. 1002 23


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