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

A 39-yr-old man presented to our hospital with unexplained erythrocytosis and hypertension. His follow-up for erythrocytosis had begun 2 yr earlier in another hospital and he had been diagnosed with polycythemia rubra vera. On admission to our hospital he was hypertensive (165/95 mmHg) and, except for the presence of moon-like face and facial plethora, his physical examination was normal. His hemoglobin concentration was 19.2 g/dl, and hematocrit was 58.9% with an increased red blood cell mass of 58 ml/kg as measured by radioisotope (Cr51). Blood film, other hematological indices except for elevated leukocyte alkaline phosphatase score, arterial gas analysis, and examination of aspirated bone marrow were all normal. An abdominal ultrasonography showed no evidence of splenomegaly. A diagnosis of probable secondary erythrocytosis was made. Early-morning serum cortisol and 24-h urinary free cortisol concentration as well as serum ACTH were high. Serum cortisol was not suppressed by low-dose dexamethasone, but suppressed by high-dose dexamethasone. Pituitary magnetic resonance imaging showed no lesion. After inferior petrosal sinus sampling suggesting right-central ACTH secretion, the patient underwent transnasal-transsphenoidal pituitary adenomectomy. Both hypercortisolemia and erythrocytosis regressed completely after the adenomectomy. After the operation, the patient's hemoglobin concentration and hematocrit decreased steadily, and 1 month post-adenomectomy his hemoglobin is 14.9 g/dl and hematocrit 44.8%. Thus, Cushing's syndrome should be a routine part of evaluation of unexplained polycythemia.
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PMID:Polycythemia as the first manifestation of Cushing's disease. 1909 3

Recently, the acquired mutation JAK2-V617F has been described in the majority of patients with myeloproliferative disorders (MPDs). In this study we evaluated its clinical and laboratory correlates in 166 patients with MPDs. The mutation was detected by allele-specific PCR in 119 patients: 81.4% (35/43) of those with polycythemia vera, 69.1% (77/111) of those with essential thrombocythemia and 58.1% (7/12) of those with idiopathic myelofibrosis. The patients carrying the mutation were older (p=0.02) and displayed higher levels of Ht (p<0.01) and Hb (<0.01) and lower erythropoietin levels (p<0.01). Moreover, mutation-positive patients displayed a higher probability of having leucocytosis, splenomegaly and thrombotic events (three-fold, two-fold and two-fold, respectively) than mutation-negative patients. These correlations imply that the JAK2-V617F mutation may be useful for the classification and the management of patients with MPDs.
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PMID:Correlations of JAK2-V617F mutation with clinical and laboratory findings in patients with myeloproliferative disorders. 1704 48

Polycythaemia vera (PV) and essential thrombocythaemia (ET) are classified as Philadelphia-negative chronic myeloproliferative diseases. Both PV and ET are rare diseases, but the prevalence is high. Patients who have not been treated for the diseases are at great risk of morbidity and mortality as a result of thrombohaemorrhagic events. However, if patients have been well treated, their prognosis is good and life-expectancy approaches normal. This article provides diagnostic tools and flowcharts for treatment of PV and ET. Treatment of PV and ET should be risk-adjusted and individualised. Low-dose aspirin is recommended as an antiaggregative drug in both diseases. For PV, phlebotomy to control a haematocrit at <0.45 is the cornerstone in treatment, and treatment with hydroxycarbamide (hydroxyurea) or interferon (IFN)-alpha is added to reduce hypermetabolic symptoms or splenomegaly becoming cytoreductive. In ET, hydroxycarbamide and anagrelide are the most used drugs, and anagrelide may also be added in PV to reduce thrombocytosis. IFNalpha is the only myelosuppressive treatment available during pregnancy. Current controversies regarding treatment illustrate the need for more randomised clinical trials. Demonstration of over expression of the PV-1 gene and in particular the JAK-2 mutation will be novel diagnostic criteria and may have an impact for future therapy of both PV and ET.
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PMID:Polycythaemia vera and essential thrombocythaemia: current treatment strategies. 1713 2

The Philadelphia chromosome (Ph)-negative myeloproliferative disorders (MPDs) include essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and polycythemia vera (PV). All of these disorders are clonal hematologic malignancies originating at the level of the pluripotent hematopoietic stem cell. Recently, activating mutations of the intracellular cytokine-signaling molecule JAK2 have been identified in > 90% of patients with PV and in 50% of those with IMF and ET. In addition, a mutation of the thrombopoietin receptor, MPLW515L, has been documented in some patients with IMF. Both mutations activate JAK-STAT signaling pathways and likely play a role in disease progression. Both ET and PV are associated with prolonged clinical courses associated with frequent thrombotic and hemorrhagic events, and progression to myelofibrosis and acute leukemia. IMF has a much poorer prognosis and is associated with cytopenias, splenomegaly, extramedullary hematopoiesis, and bone marrow fibrosis. Stratification of risk for the development of complications from Ph-negative MPDs has guided the identification of appropriate therapies for this population. Intermediate/high-risk IMF or myelofibrosis after ET or PV is associated with a sufficiently poor prognosis to justify the use of allogeneic stem cell transplantation, which is capable of curing such patients. Reduced-intensity conditioning in preparation for allogeneic stem cell transplantation has permitted older patients with IMF to undergo transplantation with increasing success.
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PMID:Philadelphia chromosome-negative myeloproliferative disorders: biology and treatment. 1722 72

The Val617Phe point mutation of Janus kinase 2 gene is believed to participate in the pathogenesis of myeloproliferative syndrome characterised by the clonal alteration of hematopoietic stem cells. According to current results, the frequency of Val617Phe activating mutation is around 80% in polycythaemia vera, 35% in essential thrombocythemia, and 50% in chronic idiopathic myelofibrosis. The diagnoses of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis were so far based on the exclusion of secondary factors as well as bone marrow biopsy histology. The goal of the present work was to establish simple molecular genetic techniques for the routine testing of Janus kinase 2 gene Val617Phe mutation, and to compare the clinical phenotypes of Val617Phe mutation positive and negative myeloproliferative syndromes. We employed the allele specific polymerase chain technique for detection of Val617Phe mutation in 252 patients with myeloproliferative syndrome. We measured Val617Phe frequency as 85,4% (117/137) in polycythemia vera, 56,6% (56/99) in essential thrombocythemia, and 87,5% (14/16) in idiopathic myelofibrosis. We found significantly elevated hemoglobin levels and white blood cell counts (measured at the time of diagnosis) in Val617Phe-positive polycythemia vera and essential thrombocythemia patient groups compared to Val617Phe-negative patients. However, the frequencies of splenomegaly and other complications (thrombosis, bleeding, transformation to acute leukemia) were not significantly different between the mutation-positive and negative groups. In conclusion, the non-invasive mutation analysis of the Janus kinase 2 Val617Phe is suitable for routine laboratory application and helps the differential diagnosis of myeloproliferative syndrome. Although the exact role of Val617Phe mutation testing has not yet been identified on the basis of a broad professional consensus, the testing is suggested in cases of erythrocytoses and thrombocytoses of unknown origin.
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PMID:[Role of the activating mutation Val617Phe of Janus kinase 2 gene in myeloproliferative diseases and significance of its detection]. 1734 40

An increase in Hb levels, haematocrit or the absolute number of red blood cells may be evidence of polycythemia rubra vera. Much more commonly, however, erythrocytosis is due to an underlying non-hematological disease. To establish the diagnosis of polycythemia, a secondary polyglobulia must first be excluded. If no evidence of polyglobulia is found, or if EPO levels are decreased, or splenomegaly not accountable for by portal hypertension is present, a specific diagnostic work-up must be performed by a hematologist/oncologist. This includes a bone marrow aspiration, cytological examination and molecular genetic testing.
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PMID:[Elevated Hemoglobin--polyglobulia or polycythemia?]. 1766 75

An acquired JAK2 V617F mutation is found in most patients with polycythemia vera (PV), and about half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Mice transplanted with bone marrow cells in which JAK2 V617F was retrovirally expressed developed PV-like features, but not ET or PMF. To address the contribution of this mutation to the pathogenesis of these three MPDs, we generated two lines of JAK2 V617F transgenic mice. One line showed granulocytosis after 4 months of age. Among 43 mice, 8 (19%) showed polycythemia and 15 (35%) showed thrombocythemia. The second line showed extreme leukocytosis and thromobocytosis. They showed anemia that means Hb value from 9 to 10 g per 100 ml when 1 month old. Myeloid cells and megakaryocytes were predominant in the bone marrow of these animals, and splenomegaly was observed. The expression of JAK2 V617F mRNA in bone marrow cells was 0.45 and 1.35 that of endogenous wild-type JAK2 in the two lines, respectively. In vitro analysis of bone marrow cells from both lines showed constitutive activation of ERK1/2, STAT5 and AKT, and augmentation of their phosphorylations by cytokine stimulation. We conclude that in vivo expression of JAK2 V617F results in ET-, PMF- and PV-like disease.
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PMID:Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. 1803 15

The JAK2(V617F) mutation was found in most patients with myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We have generated transgenic mice expressing the mutated enzyme in the hematopoietic system driven by a vav gene promoter. The mice are viable and fertile. One line of the transgenic mice, which expressed a lower level of JAK2(V617F), showed moderate elevations of blood cell counts, whereas another line with a higher level of JAK2(V617F) expression displayed marked increases in blood counts and developed phenotypes that closely resembled human essential thrombocythemia and polycythemia vera. The latter line of mice also developed primary myelofibrosis-like symptoms as they aged. The transgenic mice showed erythroid, megakaryocytic, and granulocytic hyperplasia in the bone marrow and spleen, displayed splenomegaly, and had reduced levels of plasma erythropoietin and thrombopoietin. They possessed an increased number of hematopoietic progenitor cells in peripheral blood, spleen, and bone marrow, and these cells formed autonomous colonies in the absence of growth factors and cytokines. The data show that JAK2(V617F) can cause MPDs in mice. Our study thus provides a mouse model to study the pathologic role of JAK2(V617F) and to develop treatment for MPDs.
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PMID:Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice. 1833 77

It has been suggested that polycythemia vera (PV) could be preceded by an "early" phase of the disease (e-PV), in which the increase in the red cell parameters is lower than required for a PV diagnosis. In this study, we compared the clinicopathologic and molecular features of 17 patients with e-PV with those of 14 patients with essential thrombocythemia (ET) and 19 with PV. The results for e-PV were more similar to those for PV than for ET. In fact, patients with e-PV were characterized by an increase in the red cell parameters, splenomegaly (P<.05), and hepatomegaly (P=.038), together with hypercellular bone marrow due to increased erythropoiesis and granulopoiesis, associated with megakaryocytic hyperplasia, with pleomorphic aggregates (P<.001). The frequency of the JAK2V617F mutation was similar in e-PV (16 cases tested [100%]) and PV (18/19 [95%]) but was significantly lower (7/13 [54%]) in ET (P=.0007). We propose a diagnostic algorithm helpful to distinguish ET from the early prepolycythemic phase of PV.
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PMID:The significance of bone marrow biopsy and JAK2V617F mutation in the differential diagnosis between the "early" prepolycythemic phase of polycythemia vera and essential thrombocythemia. 1870 5

Interferon (IFN) was the first cytokine discovered 50 years ago, with a wide range of biological properties, including immunomodulatory, proapoptotic and antiangiogenic activities, that rapidly raised interest in its therapeutic use in malignancies. IFN-receptor characterization was also pivotal in the discovery of the JAK/STAT signaling pathway. Among the large IFN family, mainly one of the type I IFN, IFN-alpha2, is used in therapy. Many clinical trials have shown remarkable efficacy of IFN-alpha in bcr-abl-negative myeloproliferative neoplasms (MPNs), especially polycythemia vera (PV), and essential thrombocythemia (ET). IFN-alpha induces about 80% of hematological responses in those diseases and is able to reduce splenomegaly, as well as relieve pruritus and other constitutional symptoms. Yet its use was limited by toxicity, leading to early treatment discontinuation in about 20% of the patients. However, its lack of leukemogenic potential and its possible use during pregnancy have already made IFN-alpha the drug of choice for younger MPN patients. In addition, several studies have shown a probably selective effect of IFN-alpha on PV and ET clones, as shown by cytogenetic remissions, reversions to polyclonal hematopoiesis, and more recently by induction of JAK2V617F complete molecular remissions in PV which may widen the indications of IFN-alpha in JAK2-mutated MPN.
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PMID:Interferon-alpha therapy in bcr-abl-negative myeloproliferative neoplasms. 1884 85


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