Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0032463 (polycythemia vera)
 3,374 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increasing evidence for pathological erythroid clones and availability of additional diagnostic criteria suggest to reconsider the classification of polycythemia, with particular regard to the separation between primary proliferative polycythemia (PPP) or polycythemia vera, and other conditions in which the excessive red cell mass is not due to a myeloproliferative disorder. The characteristics of the abnormal erythropoietic clone in PPP are reviewed, with special reference to the in vitro growth of Epo-independent clones and the response to Epo and other growth factors. Traditional PPP diagnostic criteria are thus integrated with more recent parameters and the clinical features are considered; the main features of idiopathic erythrocytosis (IE) are also reviewed, as well as those of other forms, like familial, secondary and apparent polycythemia. It is pointed out that previously obscure forms are now being elucidated, with the decisive help from molecular biology investigations, allowing the discovery of genetic defects. It is thus becoming apparent that basic science acquisitions, as in the field of erythropoietic initiators (Epo receptor, GATA-1 transcription factor and so on) are eventually helping our understanding of clinical problems in this area, with relevant consequences on diagnosis and treatment of various forms of polycythemia.
 ...
PMID:Polycythemia: from clones to clinic. 817 29

The discovery of high hemoglobin and hematocrit values in a patient necessitates the determination of the red blood cell mass in order to confirm the absolute character of the polycythemia. If a true polycythemia is confirmed, its etiology must then be established. The diagnostic approach of polycythemia is presented in this paper. It is illustrated by a case presentation in which a polycythemia secondary to a renal carcinoma is discussed. Erythrocytosis is a classical, albeit rare manifestation of this type of tumor, and has the advantage of allowing early detection. Thus, it permits a prompt treatment plan, thereby improving the prognosis of such a neoplasia. The usefulness of a serum level of erythropoietin (EPO) is subsequently discussed. The diagnostic value of EPO remains controversial because of the overlapping values recorded amongst healthy patients, patients with polycythemia vera and others with secondary polycythemia. Finally, we discuss the presence of substances in paraneoplastic polycythemias whose biological activity is close to that of EPO. However, this molecules of a different structure would not be detected by the radioimmunoassay used to measure erythropoietin level.
 ...
PMID:[Secondary polycythemias: the role of erythropoietin]. 827 12

A case of posttransplant erythrocytosis in a 51-year-old diabetic man is described. This problem, which can occur in 5 to 15% of renal transplant patients, can result from a contracted plasma volume (diuretics, pressure natriuresis, or glycosuria) or from a true elevation in red blood cell mass. Once the diagnosis of true erythrocytosis is made by a radiolabeled red blood cell mass study, secondary causes such as hypoxia, liver disease, polycythemia rubra vera, renal artery stenosis, and cystic kidney disease should be excluded. Posttransplant erythrocytosis has only been observed in renal transplant recipients and appears to be more frequent with cyclosporine compared with azathioprine therapy. An inappropriately high level of erythropoietin has been described in some, but not all patients, suggesting stimulation of erythropoietin production as the mechanism. Posttransplant erythrocytosis can be associated with an increased incidence of thrombotic events. The presence of this potential complication has prompted intervention to maintain the hematocrit below 50 to 55%. Measures such as discontinuation of diuretics as well as better control of blood pressure and plasma glucose should be used to facilitate the correction of extracellular volume contraction. Phlebotomy has been the most accepted intervention to intermittently lower the hematocrit when needed, but this can lead to iron deficiency. Newer therapeutic modalities are now being used to treat the problem medically. Theophylline, which reduces adenosine-mediated erythropoietin synthesis, is effective but may be associated with side effects.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Posttransplant erythrocytosis: case report and review of newer treatment modalities. 831 81

Five patients with erythrocytosis associated with renal failure on maintenance hemodialysis were investigated for in vitro erythroid progenitor growth and the effect of their uremic sera on normal erythropoiesis. The duration of hemodialysis prior to discovery of erythrocytosis ranged from 1 week to 96 months. None had acquired cystic disease and no other known cause of increased erythropoietin (Epo) production was identified. With the presence of Epo in cultures, all five patients grew erythroid colonies within normal or higher than normal ranges. Three patients formed spontaneous erythroid colonies in the absence of added Epo; all three fulfilled the clinical diagnosis of polycythemia vera (PV). The uremic sera from patients with PV lacked either a stimulating or an inhibiting effect on normal erythropoiesis. The association between renal failure and PV was coincidental. The other two patients without endogenous erythroid colony formation had enhanced erythropoietic activity in their sera, which increasingly stimulated the erythroid colony growth by normal bone marrow cells as the concentration of the uremic serum was increased. The etiology of increased Epo production in these 2 patients remained undefined during long-term follow-up. The present study on five uremic patients with polycythemia showed two different underlying mechanisms of erythrocytosis--characteristic autonomous erythroid proliferation for PV in three patients and inappropriate idiopathic Epo production in two patients.
 ...
PMID:Erythrocytosis in patients with renal failure on hemodialysis: study of underlying mechanism by in vitro erythroid culture assay. 833 Jun 48

We evaluated a newly developed enzymeimmunoassay for serum erythropoietin (Epo) and investigated relationship between Epo levels and hematological disorders. This method has several advantages including simplicity, high sensitivity, good precision. Moreover, the procedure requires only about 2.5 hours. Samples from 134 healthy subjects showed a normal logarithmic distribution, and its normal range was 4.5 approximately 21.3 mU/ml. The levels of Epo in normal subjects and various hematological disorders were as follows: 10.5 +/- 4.1 (mean +/- SD mU/ml) in normal subjects, 2.2 +/- 1.7 in polycythemia vera (PV), 6.1 +/- 3.1 in essential thrombocythemia, 17.8 +/- 27.3 in chronic myelogeneous leukemia, 3.6 +/- 1.8 in stress erythrocytosis, 39.4 and 14.1 in two cases of primary myelofibrosis, 1289 +/- 4798 in iron deficiency anemia and 6564 +/- 10870 in aplastic anemia. In patients with PV, serum Epo were low and did not correlate with hemoglobin concentration. However, inverse correlation was found between changes of Epo levels and hemoglobin levels in most patients. In cases in which PV progressed into myelofibrosis, anemia developed and Epo levels increased accordingly. These results suggest that the method is thought to be useful and reliable for the diagnosis and monitoring of PV and related hematological disorders.
 ...
PMID:[Evaluation of a one step sandwich enzymeimmunoassay for serum erythropoietin--serum erythropoietin values in polycythemia vera and related hematological disorders]. 835 12

The renal blood flow (RBF) of patients with polycythemia rubra vera is increased despite the high hematocrit (Hct) which elevates the whole blood viscosity. Since blood viscosity determines the shear force on the endothelium which is a major stimulus to nitric oxide (NO) release, we investigated the hypothesis that renal vasodilation during erythropoietin-induced erythrocytosis is mediated by the L-arginine-NO pathway. Groups of Sprague-Dawley rats received thrice weekly injections of erythropoietin (E) for two to five weeks; responses were contrasted with normal rats (N) which received sham injections. The first group was studied after five weeks of erythropoietin injections which led to sharp increases in Hct (E: 72 +/- 3 vs. N: 44 +/- 1%) and mean arterial pressure (MAP: 126 +/- 3 vs. 107 +/- 3 mm Hg). These rats had an elevated basal RBF whether measured by the clearance and renal extraction of PAH or by a transit-time renal blood flow meter. Subsequent groups were studied after two to three weeks of erythropoietin which raised the Hct more modestly to 59 +/- 2%. In this group, the basal MAP was similar in E and N rats. Graded doses of the NO synthase inhibitor, N omega-monomethyl-L-arginine (L-NMA) led to a steeper rise in MAP in E than N; at the highest doses, the MAP had increased by 36 +/- 2 in E and 23 +/- 3 mm Hg in N (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Nitric oxide mediates renal vasodilation during erythropoietin-induced polycythemia. 837 85

Human erythroid malignancies (polycythemia vera [PV] and erythroleukemia) are associated with erythropoietin (Epo)-independent growth and differentiation. Missense or nonsense mutations in the Epo receptor (Epo-R) have been recently described in experimental erythroleukemia in mice and in cases of erythrocytosis in humans. To search for a similar genetic alteration in erythroleukemia and PV, we entirely sequenced the exons of the Epo-R gene as well as the intron-exon junctions in these disorders using polymerase chain reaction. In 1 of 10 cases of erythroleukemia, a single allele mutation was found in the 8th Epo-R gene exon that changed asparagine 487 into a serine. No Epo-r gene mutation was found in 12 PV cases studied, but the same mutation (N487S) was found in 1 patient with polycythemia that did not fulfill the criteria of PV (polycythemia of unknown origin). We did not detect this mutation after sequencing part of the 8th exon of the Epo-R gene from 21 other patients with polycythemia of unknown origin and 51 normal controls. The Epo-R mutation was also found in Epstein-Barr virus-derived cell lines from both cases, suggesting that it is not related to the malignant clone. Therefore, this mutation does not appear to be somatic, although no familial cases were found. The biologic effect of this mutation was subsequently studied. Erythroid progenitors from the polycythemic patient normally responded to Epo, whereas those from the erythroleukemic patient were Epo-independent due to autocrine stimulation by Epo. The normal and the mutated Epo-R were transfected into the murine Ba/F3 cell line. Both types of cells displayed the same response to Epo for proliferation, differentiation, and inhibition of apoptosis. Although this mutation may destroy a consensus binding site for Grb2, no obvious differences either in the pattern of Epo-induced tyrosine phosphorylated proteins or in the binding of Grb2 to the Epo-R were observed. In conclusion, a somatic Epo-R missense mutation does not appear to be a molecular mechanism involved in the abnormal growth of human erythroleukemia and PV. However, the Epo-R mutation (N487S) that we describe is located in the same tyrosine sequence beginning at AA 485 as the one previously observed (P488S) in as case of polycythemia (Sokol et al, Exp Hematol 22:447, 1994). These results suggest that this phosphopeptide sequence may play an important role in Epo signalling.
 ...
PMID:Missense mutation of the erythropoietin receptor is a rare event in human erythroid malignancies. 860 41

We conducted a prospective study on 81 consecutive patients who had a kidney transplant with graft function for over 3 months to evaluate the prevalence of erythrocytosis following renal transplantation (PTE) and its potential risk factors. True PTE was defined as a RBC mass > 120% of the theoretical value allowing for sex, weight and height. 18 patients (22.2%) developed PTE (RBC mass = 157 +/- 21%) with no evidence of polycythemia vera (PV), or secondary polycythemia due to reduced arterial oxygen, kidney or hepatic tumors. PTE was more common in males (p = 0.041) and less common in patients treated with recombinant erythropoietin (rHEPO) prior to transplantation. 18 non-polycythemic patients (Hb 12.6 +/- 1.3 g/dl) matched for sex, age and renal function were used as case controls. Fewer PTE patients were transfused post-transplantation (p = 0.026). At the time of diagnosis, mean serum EPO was normal and similar to that of controls. PTE patients had lower serum ferritin (p = 0.005) and more commonly received iron supplementation when PTE occurred (p = 0.003). Other clinical factors did not differ significantly between the two groups. Two patients had a thrombotic event, 6 recovered spontaneously and 11 were successfully treated with angiotensin-converting enzyme inhibitors (ACEI). The normalization of Hb, hematocrit and RBC mass in ACEI treated patients was accompanied by a decline in serum EPO (p = 0.008). We conclude that true erythrocytosis is prevalent in cyclosporine-treated renal transplant patients. PTE seems to be an idiopathic erythrocytosis. Pretransplant rHEPO treatment may limit PTE by blunting the increased sensitivity of erythroid precursors to EPO and iron supplementation, which stimulates the development of PTE. ACEI treatment is effective and safe.
 ...
PMID:Factors predisposing to post-renal transplant erythrocytosis. A prospective matched-pair control study. 912 2

The term familial and congenital polycythemia encompasses a heterogeneous group of disorders with the common characteristic of an absolute increased red cell mass since birth and/or similar phenotype also present in relatives. In the last 2 decades the differential diagnosis between primary and secondary familial polycythemias became more physiologically relevant as new sensitive techniques, such as accurate measurements of serum erythropoietin (S-EPO) concentration by radioimmunoassay (RIA) or ELISA, and assessment of growth of erythroid progenitor cells in vitro became available. Consequently, correct classification of many older previous reports of familial polycythemias is difficult. While familial secondary polycythemias due to high oxygen affinity hemoglobin mutants are not infrequent and have been well delineated in terms of molecular pathophysiology and phenotype during the last 3 decades, those secondary familial polycythemias due to 2,3 DPG deficiency are very rare. Familial and congenital polycythemias with increased EPO concentration and normal arterial oxygen saturation and oxygen dissociation kinetics represent an intriguing group of disorders wherein the molecular lesions remain obscure; however, in some instances a possibility of abnormal oxygen sensing pathway involving hypoxia inducible factor-1 (HIF-1) open an intriguing yet unexplored area of hematology and biology. In contrast the primary familial and congenital polycythemia (PFCP) has been only recently recognized (the first report published in 1977). Various designations have been used in the past to describe PFCP, a rare clinical syndrome, including: benign familial erythrocytosis, polycythemia vera of childhood, primary polycythemia, pure erythrocytosis, etc. Some of these terms stressed the relatively benign, non-progressive course of the disease with a normal lifespan of affected subjects; however, the apparent benignity of some of these disorders has been questioned. These disorders are familial and/or congenital, and the clinical and laboratory evidence of secondary polycythemias must be excluded. Only about 2 dozen familial and sporadic cases with PFCP have been reported. However, the mutations of erythropoietin receptor (EPOR) found in some of families with PFCP represent the only defined molecular defect of primary polycythemic phenotypes. All reported PFCP associated EPOR mutations result in truncation of its intracytoplasmic C-terminal domain which negatively regulates the EPO/EPOR signal transduction pathway. Subjects with these mutations have decreased or normal S-EPO and increased sensitivity of erythroid progenitor cells to low EPO concentrations in in vitro assays. Mutations of other genes involved in post EPOR signaling pathway such as JAK-2, HCP and STAT 5 may also play a causative role in pathogenesis of some of PFCP families where mutation of EPOR was not found.
 ...
PMID:"Benign erythrocytosis" and other familial and congenital polycythemias. 898 88

Previously, we found that, in the myeloproliferative disorder polycythemia vera (PV), circulating erythroid progenitor cells were hypersensitive to insulin-like growth factor I (IGF-I), an effect shown to occur through the IGF-I receptor. Also, in cells of PV patients, the IGF-I receptor was hyperphosphorylated on tyrosine residues under basal conditions, and its tyrosine phosphorylation in response to exogenous IGF-I was strongly augmented. Thus, because IGF-I appeared to play a role in the pathogenesis of PV, we wished to assess its level in the circulation of these patients. Normally, most of the circulating IGF-I is bound to specific high-affinity IGF binding proteins that can regulate its activity. We determined the circulating levels of IGF-I and two of its key binding proteins, IGFBP-1 and IGFBP-3. In two separate experiments, plasma samples from a total of 23 PV patients age- and sex-matched with 41 normal individuals were compared by radioimmunoassay. The levels of IGFBP-1 in patients with PV (37.80 +/- 4.33 microg/L) were more than fourfold higher than in normals (9.34 +/- 1.34 microg/L) or patients with secondary erythrocytosis (9.47 +/- 1.96 microg/L), whereas the plasma concentrations of IGFBP-3 and IGF-I in these patients were similar to those of normal subjects. Because circulating IGFBP-1 levels may be influenced by insulin, we measured the concentrations of insulin in the same samples. Our data showed that the elevation of circulating IGFBP-1 in PV could not be attributed to low levels of insulin in these patients. The substantial increase in concentration of IGFBP-1 was confirmed on ligand blots performed with (125)I-IGF-I. IGFBP-1 can be either inhibitory or stimulatory to the action of IGF-I under different conditions. We reasoned that if IGFBP-1 were stimulatory for erythropoiesis, an elevated IGFBP-1 level could help to explain the increased sensitivity to IGF-I observed in PV. If IGFBP-1 were inhibitory, it might suggest a compensatory mechanism in which a hyperphosphorylated IGF-I receptor in PV might induce a negative modulator of IGF-I action, in this case IGFBP-1. To distinguish between these two hypotheses, we titrated the effect of IGFBP-1 in the presence of IGF-I with respect to erythroid burst formation and found that IGFBP-1 was strikingly stimulatory. The elevated level of IGFBP-1 coupled with its ability to stimulate erythroid burst formation provide an attractive mechanism to account for the increased sensitivity of erythroid progenitor cells to IGF-I and the consequent overproduction of red blood cells characteristic of PV.
 ...
PMID:Insulin-like growth factor binding protein-1 is elevated in patients with polycythemia vera and stimulates erythroid burst formation in vitro. 905 5


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