polycythemia vera

Introduction Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by excess production of erythrocytes, and often leukocytes and platelets, with significant symptom burden and increased risk for thrombosis, myelofibrosis (MF), and leukemic transformation. PV has an interesting history that has been previously reviewed. Important milestones include the first descriptions by Louis Henri Vaquez in 1892 and, subsequently, by William Osler, who described 4 additional cases in a series published in 1903. In 1951, William Dameshek recognized that PV shared a number of overlapping clinical and laboratory features with other “myeloproliferative disorders” (MPDs), a term he coined to classify PV, along with essential thrombocythemia (ET) and MF, which are now considered the classical MPNs. He also speculated that the MPDs shared a common pathogenesis and represented “variable manifestations of proliferative activity of the bone marrow cells.” He alluded to the presence ...

This review presents results that show that assessment of circulating neurotransmitters is the most effective and, indeed imperative, way to attain a scientific approach to the autonomic nervous system (ANS). The resulting ANS profile makes it possible to prescribe neuropharmacologic therapies to correct central nervous system circuitry disorders responsible for the abnormalities registered at the peripheral ANS level. Some examples of disastrous therapeutic trials based on poor knowledge of neuropharmacology and the ANS in general are provided. In addition, data regarding the protagonist role exerted by circulating plasma serotonin in pulmonary bronchoconstriction, pulmonary vasoconstriction, and platelet serotonin in both cardiovascular and hematological disorders are given. All of these disorders were dramatically improved by the administration of neuropharmacologic agents that affected both platelet and neuronal serotonin uptake.

Serum chitotriosidase activity (CHIT1) is a biomarker of macrophage activation with an important role in inflammation-induced tissue remodeling and fibrosis. Macrophages have been described to play a crucial role in regulating pathological erythropoiesis in polycythemia vera (PV). The aim of this study was to evaluate CHIT1 in patients diagnosed with Philadelphia-negative myeloproliferative neoplasms (MPNs). Using fluorometric assay, we measured CHIT1 in 28 PV, 27 essential thrombocythemia (ET), 17 primary myelofibrosis (PMF), 19 patients with secondary myelofibrosis and in 25 healthy controls. CHIT1 was significantly higher in PV (p < .001) and post-PV myelofibrosis (MF) transformation (post-PV MF) (p = .020), but not in ET (p = .080), post-ET MF transformation (p = .086), and PMF patients (p = .287), when compared to healthy controls. CHIT1 in PV was positively correlated with hemoglobin (p = .026), hematocrit (p = .012), absolute basophil count (p = .030) and the presence of r...

The Janus kinase 2 mutation, JAK2617V>F, is myeloid neoplasm-specific; its presence excludes secondary polycythemia, thrombocytosis, or bone marrow fibrosis from other causes. Furthermore, JAK2617V>F or a JAK2 exon 12 mutation is present in virtually all patients with polycythemia vera (PV), whereas JAK2617V>F also occurs in approximately half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Therefore, JAK2 mutation screening holds the promise of a decisive diagnostic test in PV while being complementary to histology for the diagnosis of ET and PMF; the combination of molecular testing and histologic review should also facilitate diagnosis of ET associated with borderline thrombocytosis. Accordingly, revision of the current World Health Organization (WHO) diagnostic criteria for PV, ET, and PMF is warranted; JAK2 mutation analysis should be listed as a major criterion for PV diagnosis, and the platelet count threshold for ET diagnosis can be l...

Objective(s): Functional imaging presents a non-invasive process that may capture the hyper-metabolic nature of red bone marrow in myeloproliferative neoplasms, such as polycythemia vera (PV). Methods: This study analyzed the FDG-PET/CT scans (n=12) of six patients diagnosed with PV and six age-sex matched controls using a quantitative global analysis methodology. Results: All PV patients had elevated activities in the bone marrow of each skeletal structure as compared to matched controls with respect to mean standardized uptake value (femoral neck p=0.01, lumbar spine p=0.02, pelvis p=0.002, sternum p=0.04). Notable variations in splenic uptake were observed among the treated and untreated PV patients. Conclusion: Our study exemplifies the potential utility of PET in reflecting hyperactive bone marrow activity related to PV. Future studies may further substantiate and elaborate on the use of PET-derived metabolic data in PV.

Despite recent advances in the investigation of myeloproliferative neoplasms (MPN), the impact of genetic heterogeneity on its molecular pathogenesis has not been fully elucidated. Thus, in this study, we aim to characterize the genetic complexity in Korean patients with polycythemia vera (PV) and essential thrombocythemia (ET). We conducted association studies using 84 single-nucleotide polymorphisms (SNPs) in 229 patients (96 with PV and 133 with ET) and 170 controls. Further, whole-genome sequencing was performed in six patients (two with JAK2 V617F and four with wild-type JAK2), and putative somatic mutations were validated in a further 69 ET patients. Clinical and laboratory characteristics were also analyzed. Several germline SNPs and the 46 haplotype were significantly associated with PV and ET. Three somatic mutations in MPDZ, IQCH, and CALR genes were selected and validated. The frequency of the CALR mutation was 58.0% (40/69) in ET patients, who did not carry JAK2/MPL mutations. Moreover, compared with JAK2 V617F-positive patients, those with CALR mutations showed lower hemoglobin and hematocrit levels (P = 0.004 and P = 0.002, respectively), higher platelet counts (P =0.008), and a lower frequency of cytoreductive therapy (P = 0.014). This study was the first comprehensive investigation of the genetic characteristics of Korean patients with PV and ET. We found that somatic mutations and the 46 haplotype contribute to PV and ET pathogenesis in Korean patients.

BACKGROUND AND OBJECTIVES Detection of chromosomal abnormalities in myeloproliferative disorders is important for proper diagnosis of these disorders. This study has investigated the presence of JAK2 mutation (V617F) in Egyptian patients with myeloproliferative disorders referred to National Cancer institute, Cairo University. METHODS The study involved 110 cases of Philadelphia negative Myeloproliferative diseases (MPDs), 70 cases with Polycythemia Vera (PV), 24 cases with Essential Thrombocytosis (ET) and 16 cases with Idiopathic Myelofibrosis (IMF) and 20 cases as a control group which represented as; (10 cases with secondary erythrocytosis, 1 case with reactive thrombocytosis, 4 cases as normal control and 5 as Philadelphia positive Chronic Myeloid Leukemia cases), they were collected from National Cancer Institute (NCI) over 3 years. We used ARMS technique for mutation detection. RESULTS The frequency of the V617F JAK2 mutation was highest in patients with PV where 56 out of 70...

v Abstract Polycythemia vera (PV) is currently identified as one of the three classic, Bcr/Abl-adverse, myeloproliferative disorders (MPD), together with important thrombocythemia (ET) and also myelofibrosis with myeloid metaplasia (MMM). It is now well-established that PV stands for a clonal stem-cell process that is identified by trilineage myeloproliferation, splenomegaly, thrombohemorrhagic difficulties, aquagenic pruritus, and a propensity for clonal advancement into either acute myeloid leukemia (AML) or MMM. Typical age at diagnosis is approximately 60 years and also typical life expectancy with contemporary therapy methods 20 years. The latter represents a significant renovation over historic controls, where premature death from thrombotic difficulties reduced survival to a median of less than 2 years. Present agreement debts the restorative use of hostile phlebotomy as being largely responsible for this remarkable change in survival. Nevertheless, the antithrombotic value of phlebotomy has actually not been appropriately assessed in a controlled setting, whereas randomized clinical tests have actually shown substantial reduction in vascular occasions when phlebotomy was supplemented with either myelosuppressive therapy or low-dose aspirin. In conlcusion , Physicians have for many years relied upon dimension of the RCM for the diagnosis of PV. Quantitative reference varieties are utilized to define normality, as a needed examination for the diagnosis of PV. To date, no systematic evidence sustains such technique as well as novel diagnostic assays, which are based upon disease biology, are being created and also their clinical energy verified.

The diagnosis of polycythemia vera (PV) is based on clinical and biological criteria defined by either the Polycythemia Vera Study Group (PVSG) or the World Health Organization (WHO). Both the PVSG and WHO PV criteria have proved helpful and are extensively used, yet diagnostic strategies and scheduling of biological investigations vary. We assessed the value of measuring serum erythropoietin (Epo) as a first intention diagnostic test in patients with absolute erythrocytosis (AE). Serum and bone marrow (BM) samples of 241 patients with a suspicion of erythrocytosis were collected in 8 hospital centers. One hundred and ninety had an absolute erythrocytosis (116 had PV, 66 had secondary erythrocytosis and 4 had idiopathic erythrocytosis). Serum Epo was assayed (ELISA) in 186. Statistical analysis (ROC curves) was used to define serum Epo thresholds that were specific for PV and secondary erythrocytosis and to analyze the diagnostic value of a low or high serum Epo level. A large major...

We report the case of a 59 year old woman who presented with a six week history of worsening bifrontal
headache. On CT brain the only abnormal finding was a partially empty sella potentially indicative of
increased intracranial pressure. MRI found a large cerebral venous sinus thrombosis in the superior sagittal
sinus. Blood tests and a bone marrow biopsy revealed a diagnosis of JAK2 positive primary polycythaemia
rubra vera. The lack of sensitivity and specificity of CT in the diagnosis of CVST should
engender a low threshold for MRI in patients with risk factors and/or non-diagnostic abnormalities on
initial CT. Management of this dual pathology involves both the immediate treatment of the thrombus
with heparin bridging to warfarin and the long treatment for polycythaemia involving repeat venesections
and cytoreductive therapy.

ANTECEDENTES: la mutación JAK2 V617F se ha encontrado en la mayoría de pacientes con neoplasias mieloproliferativas crónicas, por lo que se incluye en los nuevos criterios diagnósticos; sin embargo, pocos estudios las analizan en población latinoamericana, donde no son tan frecuentes.
OBJETIVO: describir las implicaciones clínicas y de pronóstico de la
mutación JAK2 V617F en una cohorte de pacientes con las siguientes
neoplasias mieloproliferativas crónicas: policitemia vera, trombocitemia
esencial y mielofibrosis primaria.
MATERIAL Y MÉTODO: estudio retrospectivo, observacional, analítico
y descriptivo de pacientes con neoplasias mieloproliferativas crónicas
atendidos de 2001 a 2014 que contaran con resultado del estudio para
identificar la mutación JAK2 V617F.
RESULTADOS: se incluyeron 38 pacientes: 55% (n=21) con trombocitemia esencial, 32% (n=12) con mielofibrosis primaria y
13% (n=5) con policitemia vera. JAK2 V617F se reportó en 45% (n=17) de los casos. La ausencia o existencia de JAK2 V617F no influyó en el cuadro clínico inicial. La media de supervivencia general fue de 110.5±15 meses. No se reportaron defunciones en los pacientes sin la mutación analizada (12 años de seguimiento), contra una media de supervivencia de 6.1 años en los portadores de JAK2 V617F (prueba log-rank, p=0.015), aunque al subanalizar la supervivencia de cada neoplasia mieloproliferativa crónica no hubo diferencia significativa.
CONCLUSIONES: la detección de JAK2 V617F facilita el diagnóstico
e incluso se dispone de tratamientos dirigidos a este blanco; sin embargo, en la población mexicana no es tan frecuente su manifestación, por lo que deben ampliarse más las investigaciones al respecto.

The diagnosis of polycythemia vera (PV) is based on clinical and biological criteria defined by either the Polycythemia Vera Study Group (PVSG) or the World Health Organization (WHO). Both the PVSG and WHO PV criteria have proved helpful and are extensively used, yet diagnostic strategies and scheduling of biological investigations vary. We assessed the value of measuring serum erythropoietin (Epo) as a first intention diagnostic test in patients with absolute erythrocytosis (AE). Serum and bone marrow (BM) samples of 241 patients with a suspicion of erythrocytosis were collected in 8 hospital centers. One hundred and ninety had an absolute erythrocytosis (116 had PV, 66 had secondary erythrocytosis and 4 had idiopathic erythrocytosis). Serum Epo was assayed (ELISA) in 186. Statistical analysis (ROC curves) was used to define serum Epo thresholds that were specific for PV and secondary erythrocytosis and to analyze the diagnostic value of a low or high serum Epo level. A large major...

Urticaria pigmentosa is a fairly indolent form of cutaneous mastocytosis, which is more prevalent in infants than in adults. Adult onset disease is usually supposed to be associated with systemic disease and has a propensity for polycythemia vera and leukaemia in a certain percentage, though regression has been reported in as many as 19% cases. A useful clue to diagnose indolent forms from malignant forms is that invariably there is thrombocytopenia with leukocytosis in malignant forms. We report an adult female with typical lesions of urticaria pigmentosa, proven by skin biopsy, who showed a good response to H1 and H2 receptor blockage treatment.

We present the case of a patient with a double transformation during the evolution of chronic hematopoietic malignancy - JAK2 positive chronic myeloproliferative neoplasm; the first transformation had occurred previous to the presentation in our Department, but the second transformation was observed in evolution and it was into a rapidly evolving disease, followed by survival of less than one month. We underline the very poor prognosis -- overall survival of 2.5 years from initial presentation -- a much reduced survival for a chronic myeloproliferative neoplasm, probably due also to multiple associated pathology. Also, the other interesting element of the case is related to the dysfunctional platelets -- hemorrhagic complication at increased platelet count, respectively thrombosis at platelet count under 20000/mmc.

Polycythemia vera (PV) and essential thrombocythemia (ET) are two Philadelphia-negative myeloproliferative neoplasms (MPN) associated with an acquired mutation in theJAK2tyrosine kinase gene. There is a rare incidence of progression to myelofibrosis and myeloid metaplasia in both disorders, which may or may not precede transformation to acute myeloid leukemia, but thrombosis is the main cause of morbidity and mortality. The pathophysiology of thrombosis in patients with MPN is complex. Traditionally, abnormalities of platelet number and function have been claimed as the main players, but increased dynamic interactions between platelets, leukocytes, and the endothelium do probably represent a fundamental interplay in generating a thrombophilic state. In addition, endothelial dysfunction, a well-known risk factor for vascular disease, may play a role in the thrombotic risk of patients with PV and ET. The identification of plasma markers translating the hemostatic imbalance in patients...

Somatic insertions/deletions in the calreticulin gene have recently been discovered to be causative alterations in myeloproliferative neoplasms. A combination of qualitative and quantitative allele-specific polymerase chain reaction, fragment-sizing, high resolution melting and Sanger-sequencing was applied for the detection of three driver mutations (in Janus kinase 2, calreticulin and myeloproliferative leukemia virus oncogene genes) in 289 cases of essential thrombocythemia and 99 cases of primary myelofibrosis. In essential thrombocythemia, 154 (53%) Janus kinase 2 V617F, 96 (33%) calreticulin, 9 (3%) myeloproliferative leukemia virus oncogene gene mutation-positive and 30 triple-negative (11%) cases were identified, while in primary myelofibrosis 56 (57%) Janus kinase 2 V617F, 25 (25%) calreticulin, 7 (7%) myeloproliferative leukemia virus oncogene gene mutation-positive and 11 (11%) triple-negative cases were identified. Patients positive for the calreticulin mutation were you...

The discovery of the JAK2V617F mutation has made the diagnosis of polycythemia vera (PV) much easier, but the pathogenesis of PV is still incompletely understood. In particular, it is not yet elucidated how a single mutation can be found in multiple myeloproliferative ...

Polycythemia and hyperhomocysteinemia are risk factors for thrombosis. Since red blood cells actively metabolize methionine to homocysteine, we investigated whether or not patients with polycythemia have increased plasma levels of homocysteine, which might contribute to their increased thrombotic risk. In ten patients with polycythemia, the plasma homocysteine levels were measured before phlebotomy, three days after the procedure and 1-2 months later. The baseline mean plasma homocysteine levels in patients (9.7 +/- 1.6 mumol/L [+/-SD]) did not differ significantly from that found in 30 sex- and age-matched healthy controls (12.2 +/- 6.9). Despite a fall in the patients' mean [+/-SD] hematocrit from 0.50 +/- 0.02 at baseline to 0.47 +/- 0.03 three days after phlebotomy (significant at 95%) and to 0.48 +/- 0.02 after 1 to 2 months (not significant), the mean plasma homocysteine levels did not change significantly (9.9 +/- 2.3 mumol/L at 3 days and 9.7 +/- 2.1 mumol/L at 1-2 month...

JAK2V617F(+) myeloproliferative neoplasms (MPNs) frequently progress into leukemias, but the factors driving this process are not understood. Here, we find excess Hedgehog (HH) ligand secretion and loss of PTCH2 in myeloproliferative disease, which drives canonical and noncanonical HH-signaling. Interestingly, Ptch2(-/-) mice mimic dual pathway activation and develop a MPN-phenotype with leukocytosis (neutrophils and monocytes), strong progenitor and LKS mobilization, splenomegaly, anemia, and loss of lymphoid lineages. HSCs exhibit increased cell cycling with improved stress hematopoiesis after 5-FU treatment, and this results in HSC exhaustion over time. Cytopenias, LKS loss, and mobilization are all caused by loss of Ptch2 in the niche, whereas hematopoietic loss of Ptch2 drives leukocytosis and promotes LKS maintenance and replating capacity in vitro. Ptch2(-/-) niche cells show hyperactive noncanonical HH signaling, resulting in reduced production of essential HSC regulators (S...

Since low JAK2V617F allele burden (AB) has been detected also in healthy subjects, its clinical interpretation may be challenging in patients with chronic myeloproliferative neoplasms (MPNs). We tested 1087 subjects for JAK2V617F mutation on suspicion of hematological malignancy. Only 497 (45.7%) patients were positive. Here we present clinical and laboratory parameters of a cohort of 35/497 patients with an AB ≤ 3%.Overall, 22/35 (62.9%) received a WHO-defined diagnosis of MPN and in 14/35 cases (40%) diagnosis was supported by bone marrow (BM) histology (''Histology-based'' diagnosis). In patients that were unable or refused to perform BM evaluation, diagnosis relied on prospective clinical observation (12 cases, 34.3%) and molecular monitoring (6 cases, 17.1%) (''Clinical-based'' or ''Molecular-based'' diagnosis, respectively). In 11/35 (31.4%) patients, a low JAK2V617F AB was not conclusive of MPN. The probability to have a final h...