Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polycythemia vera (PV) is a rare, progressive myeloproliferative disorder thought to originate from the clonal expansion of a multipotent haemopoietic stem cell. This disease is characterised by hyperproliferation of the erythroid, myeloid and megakaryocyte lineages in the early phase, anaemia and fibrosis in the spent phase, and with a significant number of patients developing acute myeloid leukaemia (AML) in the final phase. Studies investigating the growth factor requirements of committed progenitors have shown hypersensitivity to a number of haemopoietic growth factors (HGF) in vitro and several HGF receptor and signalling molecule alterations have been reported. The findings to date, however, are unable to account for the transformation of a primitive stem cell and the many alterations to growth factor responses seen in PV progenitors. Identification of the primary lesion that leads to the pathogenesis of PV is of major importance given the profound effects on regulation of the haemopoietic stem cell compartment. In this article we focus on characteristics of the disease, research findings to date and possible mechanisms to explain altered growth factor responses, receptor alterations and signalling abnormalities in PV.
 ...
PMID:Molecular aspects of polycythemia vera (review). 1093 84

Following myelo-ablative treatment and allogeneic bone marrow transplantation (BMT) in chronic myelogenous leukemia (CML) histopathological features assumed to exert a significant impact on engraftment have been rarely investigated systematically. This review is focused on immunohistochemical and morphometric techniques involving nucleated erythroid precursors, resident macrophages and their various subsets, megakaryocytes and finally argyrophilic (reticulin-collagen) fibers. Regarding standardized intervals of examination in the postgraft sequential trephine biopsies a pronounced reduction in cellularity was obvious and accompanied by a decrease in the quantity of erythro- and megakaryopoiesis. A significant correlation between the number of erythroid precursors and CD68+-macrophages could be determined in the areas of regenerating hematopoiesis. This finding is in keeping with the important functional role of the centrally localized mature macrophages during erythropoiesis. A relevant pretransplant reduction of the red cell lineage and an early to advanced reticulin fibrosis were correlated with a low hemoglobin level (anemia) and splenomegaly and furthermore associated with a significant delay to reach transfusion independence. This result was supported by corresponding findings in biopsy specimens performed shortly after day 30 following BMT (standard interval for assessment of engraftment). Samples revealed an enhancement of fiber density and a conspicuous decrease in the amount of erythropoiesis in the small fraction of patients who did not conform with the usually accepted criteria for successful hematopoietic reconstitution. Considering the compartment of histiocytic reticular cells the recurrence of Pseudo-Gaucher cells (PCGs) in the engrafted donor marrow was remarkable and most prominently expressed in the first two months following BMT. This feature was presumed to be functionally linked with a pronounced degradation of cell debris in the sequel of myelo-ablative therapy (scavenger macrophages). According to planimetric measurements in the postgraft bone marrow the atypical dwarf-like CD61+-megakaryocytes characteristic for CML disappeared. On the other hand, normalization of megakaryocyte size and nuclear lobulation were absent in sequential examination of the few patients developing a leukemic relapse. In a number of patients with manifest myelofibrosis at onset, an initial regression after BMT was followed by an insidiously occurring retrieval which was concentrated on the areas of reconstituting hematopoiesis. Similar to its relevant pretransplant association the postgraft reappearance of myelofibrosis was significantly correlated with the quantity of CD61+-megakaryocytes. Altogether a number of histological features in the pre-and postgraft bone marrow exhibited significant correlations with each other and thus indicated functional relationships. Moreover, quantity of erythropoiesis and amount of reticulin fibers (myelofibrosis) exerted a significant impact on engraftment status.
 ...
PMID:Bone marrow engraftment: histopathology of hematopoietic reconstitution following allogeneic transplantation in CML patients. 1119 98

The effect of malignant tumor growth on host's megakaryocytopoiesis and platelet production was studied in mice bearing transplantable Dalton's lymphoma. Tumor growth was paralleled by thrombocytosis, neutrophilia, and anemia. Platelet 51Cr half-life was normal but incorporation of 75Selenomethionine into circulating platelets was significantly enhanced in the tumor bearers suggesting stimulated thrombopoiesis while platelet life span remained unchanged. Megakaryocytes and their precursors, the small acetyl cholinesterase positive cells, were found in increased numbers in the bone marrow (BM) and particularly in the spleen where five to eight-fold rise was observed at the log phase of tumor growth. In addition, a remarkable increase in the number of megakaryocyte progenitors (CFU-MK and MK CFU-S) was observed both in the BM and spleen. Stimulation of these progenitors was more pronounced in the spleen than in the marrow, and the change was noticeable even from the third day of tumor bearing. Therefore, the results suggest that thrombocytosis associated with the growth of this experimental lymphoma was due to accelerated platelet production following stimulated megakaryocytopoiesis especially in the spleen.
 ...
PMID:Stimulation of megakaryocytopoiesis and platelet production during growth of an experimental lymphoma. 1127 30

Erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage stimulating factor (GM-CSF) are currently licensed for use in cancer patients and play a significant role in the management of anemia and neutropenia following myeloblative chemotherapy. EPO was the first recombinant hematopoietic growth factor to be used clinically after a number of clinical trials which demonstrated its effectiveness in treating mild to moderate cancer-associated anemia with or without concomitant chemotherapy (particulary cisplatin). An extensive research has been made for the improvement of the quality of life with EPO therapy, however, when formally assessed, variable effects of this important treatment have been observed. Recently, EPO has been shown to significantly accelerate hematopoietic reconstitution after peripheral blood stem cell transplantation (PBSCT) resulting in reduced infection rates. Both, G-CSF and GM-CSF have been shown, in numerous trials, to shorten the period of chemotherapy-induced neutropenia, with reduction in attendant morbidity and to mobilize PBSC. In addition, administration of both cytokines after PBSCT significantly reduced the use of antibiotics and duration of hospitalization suggesting an economic benefit. The narrower therapeutic window of GM-CSF at higher doses accounts for the fact that it is used much less frequently than G-CSF. To date, none of the growth factors used clinically has been shown to stimulate thrombopoiesis. Although thrombopoietin (TPO) has been found to induce megakaryocyte differentiation in vitro, it is unlikely to enter routine clinical use for treatment of post-chemotherapy thrombocytopenia, since results of clinical trials are not very encouraging, mainly because TPO is difficult to schedule and platelet aggregation may occur. Recently, innovative chimeric growth factor receptor agonists have been synthesized. Synthokine (SC-55494) (a high-affinity human IL-3 receptor ligand analog), myelopoietin (MPO) (activates human IL-3 and G-CSF receptors) and promegapoietin (PMP) (stimulates the human IL-3 and c-mpl receptors) were found to be multilineage hematopoietic growth factors and are currently undergoing clinical trials. Preliminary results suggest that these compounds may have a major impact on the management of myeloablative chemotherapy because of their ability to enhance platelet recovery in addition to their neutrophil restorative activity.
 ...
PMID:Human hematopoietic growth factors: old lessons and new perspectives. 1132 88

A new mutation is described in the X-linked gene GATA1, resulting in macrothrombocytopenia and mild dyserythropoietic features but no marked anemia in a 4-generation family. The molecular basis for the observed phenotype is a substitution of glycine for aspartate in the strictly conserved codon 218 (D218G) of the amino-terminal zinc finger loop of the transcription factor GATA1. Zinc finger interaction studies demonstrated that this mutation results in a weak loss of affinity of GATA1 for its essential cofactor FOG1, whereas direct D218G-GATA1 binding to DNA was normal. The phenotypic effects of this mutation in the patients' platelets have been studied. Semiquantitative RNA analysis, normalized for beta-actin messenger RNA, showed extremely low transcription of the GATA1 target genes GPIbbeta and GPIX but also a significantly lower expression of the nondirectly GATA1-regulated Gsalpha gene, suggestive of incomplete megakaryocyte maturation. In contrast, GPIIIa expression was close to normal in agreement with its early appearance during megakaryocyte differentiation. Flow cytometric analysis of patient platelets confirmed the existence of a platelet population with abnormal size distribution and reduced GPIb complex levels but with normal GPIIIa expression. It also showed the presence of very immature platelets lacking almost all membrane glycoproteins studied (GPIbalpha, GPIbbeta, GPIIIa, GPIX, and GPV). Patients' platelets showed weak ristocetin-induced agglutination, compatible with the disturbed GPIb complex. Accordingly, electron microscopy of the patients' platelets revealed giant platelets with cytoplasmic clusters consisting of smooth endoplasmic reticulum and abnormal membrane complexes. In conclusion, GATA1 mutations can lead to isolated X-linked macrothrombocytopenia without anemia.
 ...
PMID:Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. 1141 66

GATA1 is the X-linked transcriptional activator required for megakaryocyte and erythrocyte differentiation. Missense mutations in the N-terminal zinc finger (Nf) of GATA1 result in abnormal hematopoiesis, as documented in four families: the mutation V205M leads to both severe macrothrombocytopenia and dyserythropoietic anemia, D218G to macrothrombocytopenia and mild dyserythropoiesis without anemia, G208S to macrothrombocytopenia and R216Q to macrothrombocytopenia with beta-thalassemia. The three first GATA1 mutants display a disturbed binding to their essential transcription cofactor FOG1, whereas the fourth mutant shows an abnormal direct DNA binding. In this study, we describe a new family with deep macrothrombocytopenia, marked anemia and early mortality, if untreated, due to a different GATA1 mutation (D218Y) in the same residue 218 also implicated in the above mentioned milder phenotype. Zinc finger interaction studies revealed a stronger loss of affinity of D218Y-GATA1 than of D218G-GATA1 for FOG1 and a disturbed GATA1 self-association. Comparison of the phenotypic characteristics of patients from both families revealed that platelet and erythrocyte morphology as well as expression levels of the platelet GATA1-target gene products were more profoundly disturbed for the hemizygote D218Y mutation. The D218Y allele (as opposed to the D218G allele) was not expressed in the platelets of a female carrier while her leukocytes showed a skewed X-inactivation pattern. We conclude that the nature of the amino acid substitution at position 218 of the Nf of GATA1 is of crucial importance in determining the severity of the phenotype in X-linked macrothrombocytopenia patients and possibly also in inducing skewed X inactivation.
 ...
PMID:Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation. 1180 23

It is reported that the stay in the space develops anemia, thrombocytopenia, and altered function and structure of red blood cell. The mechanism of these abnormalities was not clarified yet. The cloning of the thrombopoietin (TPO), followed by the analysis of TPO and c-mpl (its cellular receptor) knockout mice confirmed its role as the primary regulator of thrombopoiesis. TPO has been shown to stimulate both megakaryocyte colony growth from marrow progenitor cells and the maturation of immature megakaryocyte to form functional platelet. This process includes the massive cytoskeletal rearrangement, such as proplatelet formation and fragmentation of proplatelet. In this study we have focused on the production of thrombopoietic growth factors in mice those were exposed to gravity change by parabolic flight (PF).
 ...
PMID:Effect of gravity change on the production of thrombopoietic growth factors. 1199 53

Essential thrombocythemia (ET) is a chronic myeloproliferative syndrome characterized by thrombocythemia and increased megakaryocytes in bone marrow, thrombosis and/or hemorrhagic manifestations. We report here a ten-year experience in the treatment of ET with anagrelide (A), a non mutagenic drug that inhibits megakaryocyte maturation. Between April 1991 and June 2001, 54 ET patients were included with platelet counts > 900 x 10(9)/l in asymptomatic cases and > 600 x 10(9)/l in symptomatic ones. Age at diagnosis was 39 years (11-83). Previously 30 patients had received treatment with hydroxyurea, alpha INF, busulfan and/or 32P. At diagnosis 18 patients had microvascular obstruction, 7 thrombosis, 8 hemorrhagic manifestations and 3 both hemorrhage and thrombosis. Platelet counts at diagnosis were 1200 x 10(9)/l (600-3472) and before A 995 x 10(9)/l (520-2206). The follow-up from diagnosis was 68 months (9-172) and with A treatment 34 months (2-100). The A dose during the first week of treatment was 2.5 mg/d (1-3) and at maintenance 1.5 mg/d (1-3). Complete response was obtained in 96.3% cases, 77% with platelet counts < 400 x 10(9)/l, and 18.5% < 600 x 10(9)/l. The median time to obtain a complete response was 14 days. Transient adverse effects were present in 66% of patients (headache, nausea, abdominal distention, palpitation and edema). Mild to moderate anemia developed within 2-8 months in 40% of patients. During treatment 8 patients had microvascular obstruction with platelet counts over 400 x 10(9)/l and 7 with normal values. One patient developed myelofibrosis. Five patients died for reasons unrelated to ET. In conclusion, anagrelide was effective in reducing platelet counts and preventing mayor thrombotic events.
 ...
PMID:[Treatment of essential thrombocythemia with anagrelide: a ten-year experience]. 1215 5

Fanconi anemia (FA) is a rare autosomal recessive disease, characterized by bone marrow failure and cancer predisposition. So far, 8 complementation groups have been identified, although mutations in FANCA account for the disease in the majority of FA patients. In this study we characterized the hematopoietic phenotype of a Fanca knockout mouse model and corrected the main phenotypic characteristics of the bone marrow (BM) progenitors using retroviral vectors. The hematopoiesis of these animals was characterized by a modest though significant thrombocytopenia, consistent with reduced numbers of BM megakaryocyte progenitors. As observed in other FA models, the hematopoietic progenitors from Fanca(-/-) mice were highly sensitive to mitomycin C (MMC). In addition, we observed for the first time in a FA mouse model a marked in vitro growth defect of Fanca(-/-) progenitors, either when total BM or when purified Lin(-)Sca-1(+) cells were subjected to in vitro stimulation. Liquid cultures of Fanca(-/-) BM that were stimulated with stem cell factor plus interleukin-11 produced low numbers of granulocyte macrophage colony-forming units, contained a high proportion of apoptotic cells, and generated a decreased proportion of granulocyte versus macrophage cells, compared to normal BM cultures. Aiming to correct the phenotype of Fanca(-/-) progenitors, purified Lin(-)Sca-1(+) cells were transduced with retroviral vectors encoding the enhanced green fluorescent protein (EGFP) gene and human FANCA genes. Lin(-)Sca-1(+) cells from Fanca(-/-) mice were transduced with an efficiency similar to that of samples from wild-type mice. More significantly, transductions with FANCA vectors corrected both the MMC hypersensitivity as well as the impaired ex vivo expansion ability that characterized the BM progenitors of Fanca(-/-) mice.
 ...
PMID:In vitro phenotypic correction of hematopoietic progenitors from Fanconi anemia group A knockout mice. 1220 Mar 63

Despite its wide use as a marker for hematopoietic stem cells (HSCs), the function of stem cell antigen-1 (Sca-1) (also known as lymphocyte activation protein-6A [Ly-6A]) in hematopoiesis remains poorly defined. We have previously established that Sca-1(-/-) T cells develop normally, although they are hyperresponsive to antigen. Here, we report detailed analysis of hematopoiesis in Sca-1-deficient animals. The differentiation potential of Sca-1-null bone marrow was determined from examination of the most mature precursors (culture colony-forming units [CFU-Cs]) to less committed progenitors (spleen CFUs [CFU-Ss]) to long-term repopulating HSCs. Sca-1-null mice are mildly thrombocytopenic with a concomitant decrease in megakaryocytes and their precursors. Bone marrow cells derived from Sca-1(-/-) mice also have decreased multipotential granulocyte, erythroid, macrophage, and megakaryocyte CFU (GEMM-CFU) and CFU-S progenitor activity. Competitive repopulation assays demonstrated that Sca-1(-/-) HSCs are at a competitive disadvantage compared with wild-type HSCs. To further analyze the potential of Sca-1(-/-) HSCs, serial transplantations were performed. While secondary repopulations using wild-type bone marrow completely repopulated Sca-1(-/-) mice, Sca-1(-/-) bone marrow failed to rescue one third of lethally irradiated wild-type mice receiving secondary bone marrow transplants from irradiation-induced anemia and contributed poorly to the surviving transplant recipients. These data strongly suggest that Sca-1 is required for regulating HSC self-renewal and the development of committed progenitor cells, megakaryocytes, and platelets. Thus, our studies conclusively demonstrate that Sca-1, in addition to being a marker of HSCs, regulates the developmental program of HSCs and specific progenitor populations.
 ...
PMID:Hematopoietic stem cell and progenitor defects in Sca-1/Ly-6A-null mice. 1239 91


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>