The diagnosis and management of polycythemia vera in the era since the Polycythemia Vera Study Group: a survey of American Society of Hematology members' practice patterns.
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The Polycythemia Vera Study Group (PVSG) was organized in 1967 to identify the optimal approach to the diagnosis and treatment of polycythemia vera (PV). Nevertheless, a systematic assessment of US physicians' approach to PV has not been performed. To determine practice patterns in the management of PV, a random sample of the US American Society of Hematology (ASH) membership was surveyed. Thirty-three percent of 3000 surveys were returned. Significant variations in diagnostic and therapeutic approach were evident by region, practice type, specialty, and clinical experience. Red cell volume determinations (78% of respondents), serum erythropoietin levels (76%), and arterial blood gases (75%) were the most frequent tests used in the diagnosis of PV. Sixty-nine percent of physicians use phlebotomy as their first choice for erythrocytosis. Phlebotomy plus hydroxyurea (27.8%) and hydroxyurea alone (10%) were used less often. Despite PVSG recommendations, almost 16% of physicians used a target hematocrit of 0.55 (50%) or 0.55 (55%) for phlebotomy therapy. Eighty-two percent of physicians treated thrombocytosis only when platelet counts exceeded 1000 x 10(9)/L (1 000 000/microL) or in the event of symptoms. Hydroxyurea (62.8%) and anagrelide (35.4%) were the primary agents used to treat thrombocytosis. Thus, this national survey of US hematologists and oncologists has identified substantial variation in the approach to the diagnosis and treatment of PV. A significant minority of physicians undertreat erythrocytosis, and little consensus exists regarding the treatment of thrombocytosis. (+info)
Fallot's tetralogy presenting with variceal bleed.
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The erythrocytosis of Fallot's tetralogy may lead to spontaneous thrombosis at any site, but splenic vein thrombosis and variceal bleed is rarely a presentation of Fallot's tetralogy. A case of a 48 years old female with undiagnosed Fallot's tetralogy, presenting with variceal bleed due to splenic vein thrombosis, is reported. It is also interesting to note that the patient survived till this age without any medical or surgical treatment. (+info)
Overproduction of platelet microparticles in cyanotic congenital heart disease with polycythemia.
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OBJECTIVES: We sought to clarify the role of platelets in the pathogenesis of abnormal coagulation in patients with cyanotic congenital heart disease (CCHD) with polycythemia; we evaluated the production of platelet microparticles (MPs), platelet degranulation and aggregation response, as well as the correlations of these variables with polycythemia. BACKGROUND: A shortened life span and suppressed aggregability of platelets are well known in patients with CCHD. Although platelet MPs are overproduced and play an important role in the coagulation process in various hematologic and cardiovascular disorders, the production of MPs remains to be elucidated in CCHD. We studied 19 patients who had CCHD with polycythemia and 21 age-matched subjects with acyanotic congenital heart disease (ACHD). Flow cytometry, using monoclonal antibodies, showed the presence of MPs as particles positive for the surface antigen (glycoprotein IIb/IIIa) specific to platelets, and platelet alpha-degranulation was recognized as platelets positive for the surface antigen of P-selectin. Platelet aggregation was assessed as the response to adenosine diphosphate (ADP). Relationships between these indexes and hematocrit (Hct) values were also evaluated. RESULTS: Production of MPs correlated positively with Hct and markedly increased at Hct values above 60% in patients with CCHD. Surface P-selectin and the mean platelet volume in patients with CCHD were comparable with those in patients with ACHD. The platelet aggregation response to ADP significantly and negatively correlated with Hct. In two subjects who showed hemoptysis and underwent phlebotomy, MPs were reduced 6 h after the procedure. CONCLUSIONS: Platelet MPs are overproduced in patients who have CCHD with polycythemia, probably due to a high shear stress derived from blood hyperviscosity. Circulating incompetent platelets, which have already been activated, as well as MPs, might play an important role in the coagulation abnormalities identified in such patients. (+info)
Polycythaemia and hypertension caused by renal artery stenosis.
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A girl with failure to thrive and a haemoglobin of 140 g/l at 1.3 years died from a brain haemorrhage 2.5 years later. Renal artery stenosis had caused severe, chronic hypertension and increased erythropoietin secretion (haemoglobin 182 g/l). Blood pressure should be measured in all unwell children, including those failing to thrive. (+info)
A novel mutation in the erythropoietin receptor gene is associated with familial erythrocytosis.
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Primary familial erythrocytosis (familial polycythemia) is a rare myeloproliferative disorder with an autosomal dominant mode of inheritance. We studied a new kindred with autosomal dominantly inherited familial erythrocytosis. The molecular basis for the observed phenotype of isolated erythrocytosis is heterozygosity for a novel nonsense mutation affecting codon 399 in exon 8 of the erythropoietin receptor (EPOR) gene, encoding an EpoR peptide that is truncated by 110 amino acids at its C-terminus. The new EPOR gene mutation 5881G>T was found to segregate with isolated erythrocytosis in the affected family and this mutation represents the most extensive EpoR truncation reported to date, associated with familial erythrocytosis. Erythroid progenitors from an affected individual displayed Epo hypersensitivity in in vitro methylcellulose cultures, as indicated by more numerous erythroid burst-forming unit-derived colonies in low Epo concentrations compared to normal controls. Expression of mutant EpoR in interleukin 3-dependent hematopoietic cells was associated with Epo hyperresponsiveness compared to cells expressing wild-type EpoR. (+info)
Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma.
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The von Hippel-Lindau (VHL) tumor suppressor gene targets hypoxia-inducible transcription factors (HIFs) for proteasomal degradation. Erythrocytosis due to inappropriate production of erythropoietin (EPO), one of the HIF target genes, is a classic albeit rare finding in patients with renal cancer. We report the clinical to molecular analysis in a patient in whom a thrombotic myocardial infarction was the first manifestation of a clear cell renal carcinoma associated with an elevated serum EPO level (109 U/L) and erythrocytosis (hemoglobin 200 g/L [20 g/dL]). The tumor strongly expressed EPO messenger RNA and the 2 regulatory subunits HIF-1alpha and HIF-2alpha. Sequence analysis of tumor tissue identified a point mutation of the VHL gene (nucleotide 701 T > C) with a predicted amino acid exchange (Leu163Pro). This structural change, although located at distance to the HIF-binding region, was found to inhibit binding of HIF-1alpha to VHL, thus leading to accumulation of HIF, which drives EPO production. (+info)
Paradoxical secondary polycythemia in von Hippel-Lindau patients treated with anti-vascular endothelial growth factor receptor therapy.
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Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by germline mutations in the VHL tumor-suppressor gene. Central nervous system (CNS) and retinal hemangioblastomas are highly vascular tumors that are hallmarks of the disease. These tumors overexpress vascular endothelial growth factor (VEGF) and represent a potential target for anti-angiogenic drugs. We observed, after 3 to 4 months of treatment, secondary paradoxical polycythemia in 3 VHL patients with CNS or retinal hemangioblastomas treated by the anti-VEGF receptor SU5416. Hematocrit was normal before the beginning of the trial, and no progression of hemangioblastomas was observed. Polycythemia vera and all known causes of secondary polycythemia were also ruled out. Polycythemia has never been reported in current SU5416 trials for advanced malignancies and could express a specific action on red blood cell precursors occurring only in the absence of a functional VHL gene. These findings could also affect the inclusion of VHL patients with pre-existing polycythemia in future anti-VEGF receptor trials. (+info)
Chronic hypoxia (CH) augments endothelium-derived nitric oxide (NO)-dependent pulmonary vasodilation; however, responses to exogenous NO are reduced following CH in female rats. We hypothesized that CH-induced attenuation of NO-dependent pulmonary vasodilation is mediated by downregulation of vascular smooth muscle (VSM) soluble guanylyl cyclase (sGC) expression and/or activity, increased cGMP degradation by phosphodiesterase type 5 (PDE5), or decreased VSM sensitivity to cGMP. Experiments demonstrated attenuated vasodilatory responsiveness to the NO donors S-nitroso-N-acetylpenicillamine and spermine NONOate and to arterial boluses of dissolved NO solutions in isolated, saline-perfused lungs from CH vs. normoxic female rats. In additional experiments, the sGC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, blocked vasodilation to NO donors in lungs from each group. However, CH was not associated with decreased pulmonary sGC expression or activity as assessed by Western blotting and cGMP radioimmunoassay, respectively. Consistent with our hypothesis, the selective PDE5 inhibitors dipyridamole and T-1032 augmented NO-dependent reactivity in lungs from CH rats, while having little effect in lungs from normoxic rats. However, the attenuated vasodilatory response to NO in CH lungs persisted after PDE5 inhibition. Furthermore, CH similarly inhibited vasodilatory responses to 8-bromoguanosine 3'5'-cyclic monophosphate. We conclude that attenuated NO-dependent pulmonary vasodilation after CH is not likely mediated by decreased sGC expression, but rather by increased cGMP degradation by PDE5 and decreased pulmonary VSM reactivity to cGMP. (+info)