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)

Patients with polycythemia vera (PV) are most often treated with phlebotomy-only (PHL-O) or phlebotomy plus hydroxyurea (PHL + HU). Such treatment is often unsatisfactory because of persistent susceptibility to thrombosis owing to inadequate control of abnormal erythropoiesis and thrombopoiesis. Recombinant interferon-alpha (rIFN alpha) inhibits erythroid progenitors and affects megakaryocyte function and thus may be a more effective treatment, but reports of its use have been of relatively short duration. The long-term use (median, 13 years) of rIFN alpha in 55 patients previously treated with PHL alone or with PHL + HU was studied. Data pertaining to the natural history of the disease were also examined. Patients achieved partial response of their disease by 6 months, and complete response by 1-2 years (phlebotomy-free, HCT < or =45%, platelets < or =600,000/microL); spleen size was reduced in 27 of 30 patients with prior splenomegaly. The initial dose of rIFN alpha was 1 mega unit 3 times a week (1 MU/tiw) for the majority of patients, with periodic dose increases as required and as tolerated. The maintenance dose, usually 3 MU/tiw, could be decreased after the second year of treatment in half the patients. Toxicity was acceptable. Disease-free survival was marked by no thrombohemorrhagic complications reflecting both the effect of rIFN alpha and total patient care. Evidence is presented indicating that rIFN alpha effectively reduces PHL requirements, thrombocythemia, splenomegaly, and thrombohemorrhagic events. It is an effective drug for treating PV with acceptable toxicity.
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PMID:Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. 1680 23

The selection of treatment for patients with polycythemia vera (PV) still is the subject of much discussion among hematologists. It is emphasized that important physiologic and pathogenic components of the illness relate not only to the erythroid cell, but also to the megakaryocyte. Both play essential roles in causing complications of the disease. Hematologists agree that the mainstay in treatment remains phlebotomy, a basic pillar of the concept of PRIMUM NON NOCERE. In general, the target levels for the hematocrit have been accepted as <or= 45% for men and <or= 42% for women. Low-dose aspirin, 80 to 100 mg daily, should be used as a basic component of therapy. The selection of the type of treatment for those patients who require some form of myelosuppression owing to the frequency of phlebotomy and/or its complications provides the basis for major discussion, confrontation, and disagreement. For the most part, alkylating agents are avoided owing to the established risk of secondary leukemia, but these drugs and radioactive phosphorous ( (32)P) still play a role in treating the very elderly patient or for those who have significant comorbid conditions. Whereas hydroxyurea remains the most frequently prescribed drug, limitations to its use as a therapeutic agent of choice include questions regarding its effectiveness, toxicity, and potential leukemogenicity. Interferon offers a rational choice of treatment owing to its broad physiologic effects on hematopoiesis. Whereas its effect in treating patients with PV is unequivocal, it is associated with side effects even when used properly. Moreover, it has only modest effect on Janus kinase 2 (JAK2) expression. Clearly, the best treatment for patients with PV is still sought. Perhaps more explicit exploitation of the JAK2 abnormality found in PV (and other myeloproliferative diseases) may provide more effective agents in the future.
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PMID:Treatment of polycythemia vera. 1681 Jun 20

Patients with essential thrombocythemia (ET) and polycythemia vera (PV), complicated by microvascular ischemic or thrombotic events, have shortened platelet survival, increased beta-thromboglobulin, platelet factor 4, and thrombomodulin levels, and increased urinary thromboxane B2 excretion. These are all reversible by inhibition of platelet cyclooxygenase 1 with aspirin, and are therefore indicative of platelet activation and platelet-mediated thrombotic processes. The thrombotic tendency persists as long as platelet counts are above the upper limit of normal (400 x 10 (9)/L). Despite strong evidence of in vivo platelet activation, the ex vivo platelet function tests are impaired. Platelet dysfunction in ET and PV typically is characterized by a missing second-wave adrenaline aggregation, an increased adenosine diphosphate aggregation threshold, and reduced secretion products, but a normal arachidonic acid or collagen-induced aggregation. The proposed concept is that platelets in thrombocythemia (ET and PV) are hypersensitive. Due to the existing high shear stress in the microvasculature (end-arterial circulation), platelets spontaneously activate, secrete their products, form aggregates mediated by von Willebrand factor (vWF) that transiently plug the microcirculation, deaggregate, and then recirculate as exhausted defective platelets with secondary storage pool disease on ex vivo analysis. At increasing platelet counts from below to above 1000 x 10 (9)/L, the thrombotic condition changes into an overt spontaneous bleeding tendency as a result of a functional vWF deficiency that is caused by proteolysis of large vWF multimers. This is consistent with acquired type 2 von Willebrand syndrome (AvWS). AvWS is reversible by reduction of the platelet count to normal. The acquired JAK2 V617F gain of function mutation is the cause of trilinear myeloproliferative disease with the sequential occurrence of ET and PV. Heterozygous JAK2 V617F mutation with slightly increased kinase activity is enough for the induction of spontaneous megakaryopoiesis and erythropoiesis, and an increase of hypersensitive platelets is the cause of aspirin-sensitive, platelet-mediated microvascular ischemic and thrombotic complications in ET and early PV mimicking ET. Homozygous JAK2 mutation with pronounced increase of kinase activity is associated with pronounced trilinear megakaryocyte, erythroid, and granulocytic myeloproliferation, with the most frequent clinical picture of classical PV complicated by major thrombosis, in addition to the platelet-mediated microvascular thrombotic syndrome of thrombocythemia.
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PMID:The paradox of platelet activation and impaired function: platelet-von Willebrand factor interactions, and the etiology of thrombotic and hemorrhagic manifestations in essential thrombocythemia and polycythemia vera. 1697 69

The JAK2(V617F) mutation is present in almost all patients with polycythemia vera (PV), large proportions of patients with essential thrombocythemia and idiopathic myelofibrosis, and less frequently in atypical myeloproliferative disorders (MPD). We show that transplantation of JAK2(V617F)-transduced bone marrow into BALB/c mice induces MPD reminiscent of human PV, characterized by erythrocytosis, granulocytosis, extramedullary hematopoiesis, and bone marrow fibrosis, but not thrombocytosis. Fluorescence-activated cell sorting of bone marrow and spleen showed proportional expansion of common myeloid progenitors, granulocyte-monocyte and megakaryocyte-erythrocyte progenitors. Megakaryocyte and late erythroid progenitors were dramatically increased, with only modest expansion of early erythroid progenitors. Erythropoietin (Epo) receptor expression was reduced on early, but normal on late erythroblasts. Serum levels of Epo and granulocyte colony-stimulating factor, but not granulocyte macrophage colony-stimulating factor, were reduced, whereas tumor necrosis factor-alpha was increased, possibly exerting a negative effect on JAK2(V617F)-negative hematopoiesis. These data suggest that erythrocytosis and granulocytosis in JAK2(V617F) mice are the net result of a complex interplay between cell intrinsic and extrinsic factors. There were no thromboembolic events and no animals succumbed to their disease, implicating additional factors in the manifestation of human disease. The disease was not transplantable and prolonged observation showed normalization of blood counts in most JAK2(V617F) mice, suggesting that the mutation may not confer self-renewal capacity.
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PMID:Characterization of murine JAK2V617F-positive myeloproliferative disease. 1714 59

After accounting for misdiagnosis and treatment effect, allele-specific (AS)-PCR detects the JAK2V617F mutation in >95% of polycythemia vera (PV) patients. Using database inquiry, we identified 6 of a total 220 cases with PV that were JAK2V617F-negative (prevalence=3%). Of these, five cases ( approximately 80%) were found to harbor one of the two JAK2 exon 12 mutations (F537-K539delinsL or N542-E543del) in bone marrow (BM) and/or peripheral blood cells. Similar screening of six additional cases - three each with idiopathic erythrocytosis (IE) or otherwise unexplained erythrocytosis (UE) - did not reveal either JAK2V617F or JAK2 exon 12 mutations. We found JAK2 exon 12 mutations in PV cases to be readily detected by both DNA sequencing and AS-PCR, regardless of whether BM or peripheral blood cells were used as the source for DNA. Although erythroid hyperplasia was the predominant histologic feature on BM examination, megakaryocyte abnormalities and reticulin fibrosis were noted in most PV patients harboring exon 12 mutations. However, similar BM morphologic changes can also be seen in some JAK2V617F-positive PV cases; therefore, distinct genotype-phenotype association cannot be established.
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PMID:Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. 1759 10

In the present study, we report that media conditioned by polycythemia vera (PV) CD3+ cells promote BFU-E and CFU-Mk colony formation by both cord blood and PV peripheral blood CD34+ cells in the absence of exogenous cytokines and promoting megakaryocyte proplatelet formation. CD3+ cells constitutively produce elevated levels of IL-11, while stimulation with the addition of phytohemagglutinin (PHA) increased GM-CSF levels in most of the patients with PV. Anti-IL-11-neutralizing antibody partially inhibited the formation of BFU-E and CFU-Mk colonies promoted by PV CD3+ cell-conditioned media. Although IL-11 is not produced by normal T cells, real-time PCR and flow cytometric analysis showed that IL-11 was upregulated in the CD3+ cells of most PV patients as compared to normal CD3+ cells. In addition, a greater percentage of BFU-E colonies formed by PV CD34+ cells in the presence of PV CD3+ cell-conditioned media alone were JAK2V617F-positive as compared with that induced by EPO. We conclude that dysregulated production of soluble growth factor(s), including IL-11 and GM-CSF by PV T cells, contributes to the in vitro formation of erythroid colonies in the absence of exogenous cytokines by PV CD34+ cells and likely plays a role in sustaining hematopoiesis in PV.
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PMID:T cells from patients with polycythemia vera elaborate growth factors which contribute to endogenous erythroid and megakaryocyte colony formation. 1771 53

The role of histopathology in the diagnosis of essential thrombocythemia (ET) is controversial, and there has been little attempt to quantitate interobserver variability. Diagnostic bone marrow trephine biopsy specimens from 370 patients with ET by Polycythemia Vera Study Group (PVSG) criteria were assessed by 3 experienced hematopathologists for 16 different morphologic features and overall diagnosis according to the World Health Organization (WHO) classification. Our results show substantial interobserver variability, particularly for overall diagnosis and individual cellular characteristics such as megakaryocyte morphology. Reticulin grade was the dominant independent predictor of WHO diagnostic category for all 3 hematopathologists. Factor analysis identified 3 independent factors likely to reflect underlying biologic processes. One factor related to overall and lineage-specific cellularity and was significantly associated with JAK2 V617F status (P < .001), a second factor related to megakaryocyte clustering, and a third was associated with the fibrotic process. No differences could be discerned between patients labeled as having "prefibrotic myelofibrosis" or "true ET" in clinical and laboratory features at presentation, JAK2 status, survival, thrombosis, major hemorrhage, or myelofibrotic transformation. These results show that histologic criteria described in the WHO classification are difficult to apply reproducibly and question the validity of distinguishing true ET from prefibrotic myelofibrosis on the basis of subjective morphologic criteria. This study was registered at http://isrctn.org as #72251782 and at http://eudract.emea.europa.eu/ as #2004-000245-38.
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PMID:Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes. 1788 79

Among 23 cases of myeloproliferative neoplasms (MPNs) with an associated del(5q) seen at our institution, 14 (61%) fulfilled diagnostic criteria for primary myelofibrosis (PMF). Other diagnoses included polycythemia vera (PV; n=2), essential thrombocythemia (ET; n=1), post-ET myelofibrosis (n=1), systemic mastocytosis (SM; n=1), and MPN, unclassifiable (n=4). Compared to their del(5q)-negative counterparts, del(5q)-positive PMF cases were significantly more anemic (p<0.001) and thrombocytopenic (p<0.001). However, survival and leukemic transformation rates appear to be similar between the two groups. del(5q)-positive PMF was histologically characterized by a mixture of both small and monolobated megakaryocytes as well as large and bizarre megakaryocytes. When used, lenalidomide therapy induced hematological and cytogenetic remissions in del(5q)-positive PMF. The current study identifies PMF as another del(5q)-associated myeloid malignancy with characteristic megakaryocyte morphology.
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PMID:Primary myelofibrosis is the most frequent myeloproliferative neoplasm associated with del(5q): clinicopathologic comparison of del(5q)-positive and -negative cases. 1853 39

European experts were convened to develop a definition of response to treatment in polycythemia vera (PV) and essential thrombocythemia (ET). Clinicohematologic (CH), molecular, and histologic response categories were selected. In ET, CH complete response (CR) was: platelet count less than or equal to 400 x 10(9)/L, no disease-related symptoms, normal spleen size, and white blood cell count less than or equal to 10 x 10(9)/L. Platelet count less than or equal to 600 x 10(9)/L or a decrease greater than 50% was partial response (PR). In PV, CH-CR was: hematocrit less than 45% without phlebotomy, platelet count less than or equal to 400 x 10(9)/L, white blood cell count less than or equal to 10 x 10(9)/L, and no disease-related symptoms. A hematocrit less than 45% without phlebotomy or response in 3 or more of the other criteria was defined as PR. In both ET and in PV, molecular CR was a reduction of any molecular abnormality to undetectable levels. Molecular PR was defined as a reduction more than or equal to 50% in patients with less than 50% mutant allele burden, or a reduction more than or equal to 25% in patients with more than 50% mutant allele burden. Bone marrow histologic response in ET was judged on megakaryocyte hyperplasia while on cellularity and reticulin fibrosis in PV. The combined use of these response definitions should help standardize the design and reporting of clinical studies.
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PMID:Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference. 1927 53

BCR-ABL negative myeloproliferative neoplasms (MPNs; polycythemia vera, essential thrombocythemia, primary myelofibrosis) are malignant diseases arising from a multipotent hematopoietic progenitor, frequently altered by JAK2 V617F or other JAK/STAT activating mutations. The thrombopoietin receptor (TpoR, MPL) is one of the major dimeric cytokine receptors that use JAK2 in the myeloid lineage, and was found to be down-modulated in certain MPN patients. We searched for negative regulators of MPL expression. Here we report that miR-28 targets the 3' untranslated (3'UTR) region of MPL, inhibiting its translation, as well as other proteins potentially involved in megakaryocyte differentiation, such as E2F6. Expression of miR-28 in CD34-derived megakaryocytes inhibited terminal differentiation. miR-28 was found to be overexpressed in platelets of a fraction of MPN patients, while it was expressed at constant low levels in platelets from healthy subjects. Constitutive activation of STAT5 leading to autonomous growth of hematopoietic cell lines was associated with increased miR-28 expression. We discuss how down-modulating MPL and other targets of miR-28, and of related miR-708 and miR-151, could contribute to MPN pathogenicity.
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PMID:miR-28 is a thrombopoietin receptor targeting microRNA detected in a fraction of myeloproliferative neoplasm patient platelets. 2044 18


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