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 INTERLEUKIN 1β LEVEL AND C- REACTIVE PROTEIN ROLES IN PRIMARY MYELOFIBROSIS PATIENTS TREATED WITH HYDROXYUREA AND RUXOLITINIB

 INTERLEUKIN 1β LEVEL AND C- REACTIVE PROTEIN ROLES IN PRIMARY MYELOFIBROSIS PATIENTS TREATED WITH HYDROXYUREA AND RUXOLITINIB

Primary Myelofibrosis (PMF) is a uncommon bone marrow disease in which the marrow is replaced by fibrous tissue; PMF primarily affects elderly patients [1]. The PMF develop when a change occur in the hematopoietic stem cell in DNA, In myeloproliferative neoplasm(MPN) there is progressive bone marrow fibrosis, extra medullary hematopoiesis, extreme creation of inflammatory cytokines, leading to reduced survival

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Primary myelofibrosis: spectrum of imaging features and disease-related complications

Primary myelofibrosis: spectrum of imaging features and disease-related complications

Epidemiology, clinical features, and presentations The annual incidence of primary myelofibrosis (PMF) is 0.4–1.4 per 100,000 population [2, 3] and shows a predilection for older males, although younger pa- tients can be affected. Of the MPNs, PMF is the least common [4] but is associated with poorer survival, approximately 2 to 5 years upon diagnosis and symp- tom onset [5]. Patients may be asymptomatic and present following detection of incidental radiological findings or through discovery of anaemia, thrombocy- tosis, or thrombocytopaenia. In symptomatic patients, the clinical presentation varies from constitutional symptoms [4] to cardiovascular complications related to severe anaemia and thromboembolic events. Up to 10% of patients experience a thromboembolic event, most commonly venous thromboembolism [6]. Sple- nomegaly is an inevitable outcome and may lead to splenic infarction, haemorrhage, splanchnic vein throm- bosis, portal hypertension, or mass effect symptoms [4, 7–9]. There is also a small risk of progression to acute myeloid leukaemia [10].
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MYB deregulation from a EWSR1-MYB fusion at leukemic evolution of a JAK2
                     V617F positive primary myelofibrosis

MYB deregulation from a EWSR1-MYB fusion at leukemic evolution of a JAK2 V617F positive primary myelofibrosis

Abbreviations: AML, Acute myeloid leukemia; BM, Bone marrow; DBD, DNA binding domain; DHPLC, Denaturing high performance liquid chromatography; ET, Essential thrombocytopenia; FISH, Fluorescence in situ hybridization; Hb, Haemoglobin; I-FISH, Interphase-FISH; MCV, Mean corpuscular volume; Ph-MPN, Philadelphia negative myeloproliferative neoplasia; PMF, Primary myelofibrosis; PV, Polycythemia vera; qRT-PCR, Quantitative reverse transcription-polymerase chain reaction; RT-PCR, Reverse transcription-polymerase chain reaction; SNPa, Single nucleotide polymorphism array; TAD, Transcriptional-activating domain; WBC, White blood cell
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Primary myelofibrosis associated glomerulopathy: significant improvement after therapy with ruxolitinib

Primary myelofibrosis associated glomerulopathy: significant improvement after therapy with ruxolitinib

Fig. 1 Microscopy results of kidney and liver tissue from a 60-year-old man with myeloproliferative neoplasm-related glomerulopathy in the early stages of primary myelofibrosis hematoxylin and eosin (H&E) (a) and periodic acid-Schiff (PAS) (b) stained sections of glomeruli with moderate mesangial matrix expansion and occasional intracapillary and intra-arteriolar megakaryocytes (arrows). The renal tubulointerstitium (c) also contained interstitial or intracapillary megakaryocytes (arrow). A biopsy of the liver (d) showed megakaryocytes, nucleated red blood cells and other immature myeloid cell within the hepatic sinusoids
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Rare congenital chromosomal aberration dic(X;Y)(p22.33;p11.32) in a patient with primary myelofibrosis

Rare congenital chromosomal aberration dic(X;Y)(p22.33;p11.32) in a patient with primary myelofibrosis

Background: Constitutional translocations between sex chromosomes are rather rare in humans with breakpoints at Xp11 and Yq11 as the most frequent. Breakpoints on the short arm of the Y chromosome form one subgroup of t(X;Y), giving rise to a derived chromosome with the centromeres of both the X and Y chromosomes, dic(X;Y). Here, we report a rare congenital chromosomal aberration, 46,X,dic(X;Y)(p22.33;p11.32)[20]/45,X[10], in an adult male. Case presentation: Primary myelofibrosis, a malignant haematological disease, was diagnosed in a 63-year-old man following liver transplantation after hepatocellular carcinoma. By the analysis of the bone marrow sample, the karyotype 46,X,dic(X;Y)(p22.33;p11.32) was detected in all the mitoses analysed and verified with multicolour fluorescence in situ hybridization (mFISH). A cytogenetic examination of stimulated peripheral blood cells revealed the constitutional karyotype 46,X,dic(X;Y)(p22.33;p11.32)[20]/45,X[10]. The cell line 45,X was confirmed with FISH in 35 % of interphase nuclei. The SRY locus was present on the dicentric chromosome. A CGH/SNP array (Illumina) revealed a gain of 153,7 Mbp of the X chromosome and a 803-kbp microdeletion (including the SHOX gene), which were also confirmed with FISH. SHOX encodes a transcriptional factor that regulates the growth of the long bones. The deletion of the SHOX gene together with the Madelung deformity of the forearm and the short stature of the proband led to a diagnosis of Léri-Weill dyschondrosteosis (LWD). The gain of almost the whole X chromosome (153,7 Mbp) was considered a variant of Klinefelter syndrome (KS). The levels of gonadotropins and testosterone were consistent with gonadal dysfunction. A malformation of the right external ear was detected.
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β-Arrestin2 mediates progression of murine primary myelofibrosis

β-Arrestin2 mediates progression of murine primary myelofibrosis

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) of hematopoietic stem cells (HSCs) characterized by clonal proliferation of myeloid cells and secondary marrow fibrosis. PMF patients have significant disease-related morbidity (pancytopenia, hepatosplenomegaly, constitutional symptoms, weight loss) and a 15%–20% chance of transformation to acute leukemia, which is almost uniformly fatal despite aggressive management (1, 2). Current therapeutic options are limited and include JAK inhibitors; interferons; symptom-directed therapies, including steroids and cytoreductive agents; and allogeneic stem cell transplantation. Unfortunately, highly effective therapies for this pro- gressive, debilitating disease are lacking and novel therapies are needed (3–5).
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Coexistence of primary myelofibrosis and chronic lymphocytic leukemia

Coexistence of primary myelofibrosis and chronic lymphocytic leukemia

Abstract: Coexistence of two hematologic malignancies in one patient is generally a rare phenomenon. The topic of this article is the coincidence of primary myelofibrosis and chronic lymphocytic leukemia, which has been reported up to now in only 16 patients. In summary, simultaneous detection of both diseases was notable in half of the patients at presentation. In the case of a subsequent diagnosis of both disorders, primary myelofibrosis preceded the lymphoproliferative disease in the majority of patients. The clinical course seems to be more benign than for each disorder itself. A substantial proportion of patients did not require any treatment at all. Knowledge about the pathogenetic mechanisms, treatment approaches, and prognosis of these patients is limited.
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Leukemic transformation driven by an ASXL1 mutation after a JAK2V617F-positive primary myelofibrosis: clonal evolution and hierarchy revealed by next-generation sequencing

Leukemic transformation driven by an ASXL1 mutation after a JAK2V617F-positive primary myelofibrosis: clonal evolution and hierarchy revealed by next-generation sequencing

We have characterized the molecular changes underlying the transformation of a JAK2V617F + -myelofibrosis with trisomy 8, into a JAK2V617F-negative leukemia. Leukemic clone did not carry JAK2V617F mutation, but showed ASXL1 mutation (R693X). This mutation was identified in a low percentage at diagnosis by next-generation sequencing. Using this technology in serial specimens during the follow-up, we observed a progressive expansion of the ASXL1-mutated minor clone, whereas the JAK2V617F + -clone carrying trisomy 8 decreased. Hematologic progression occurred simultaneously with an ASXL1-R693X-negative lung-cancer. This is the first report showing a clear association between the expansion of an ASXL1-mutated clone and the leukemic transformation of
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Thrombosis in essential thrombocytemia and early/prefibrotic primary myelofibrosis: the role of the WHO histological diagnosis

Thrombosis in essential thrombocytemia and early/prefibrotic primary myelofibrosis: the role of the WHO histological diagnosis

A clinico-pathologic database of patients with complete clinical data consecutively diagnosed as having ET and treated at our institution has been reviewed. This study included 283 patients with ET diagnosed since 1980 and followed up to 2011 at the Clinic of Hematology Poly- technic University of Marche Region, United Hospital of Ancona, Italy. The diagnosis of ET was originally made in accordance with the criteria in use at the time of first observation. In the present study we considered the fol- lowing parameters: age, sex, platelet count, hemoglobin level, white blood cell count, lactic dehydrogenase (LDH- evaluated in 95 patients), JAK2V617F mutation status (investigated since 2007 in 75 patients), spleen size, history of thrombosis (before and at diagnosis), pro- gression to overt myelofibrosis, conventional risk for thrombosis according to Cervantes [14]. We considered as venous and arterial thrombotic events the following: deep venous thrombosis of the extremities (DVT) or atypical thrombosis (abdominal and cerebral veins), pul- monary embolism (PE), ischemic stroke, cerebral transi- ent ischemic attack (TIA), acute myocardial infarction (AMI) and peripheral arterial thrombosis (PAT).
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<p>t(15; 17) associated with primary myelofibrosis: a case report of an unusual clinical presentation and diagnostic dilemma</p>

<p>t(15; 17) associated with primary myelofibrosis: a case report of an unusual clinical presentation and diagnostic dilemma</p>

Bone marrow morphology again demonstrated hyper- cellularity (90 – 100%) with severe fi brosis (MF Grade 3 of 3), atypical megakaryocytes and 4% blasts. Flowcytometry showed 4.9% population of intermediate to large cells with the following immunophenotype: CD7-, CD11B-, heteroge- neous CD13+, CD14-, CD15-, CD16-, dim CD33+, CD34+, CD38+, dim CD45+, subset CD56+ (expressed on 7% of the blasts), CD64-, heterogeneous CD71+, heterogeneous CD117+, HLADR+ and the fi ndings suggested clonal mye- loid neoplasm. Repeat cytogenetic analysis con fi rmed 46 XY with t(15; 17), and also showed a 20q- abnormality in 2 cells. FISH testing, however, did not reveal the PML/RARA t(15; 17) translocation in 300 cells that were analyzed. RT-PCR also did not detect PML-RARA fusion transcripts. Further doses of ATRA were held at this time because of the severe anaphylactic reaction and also now that the additional infor- mation ruled out an APL. Together, with the FISH and RT- PCR being negative for PML-RARA fusion transcripts and with bone marrow fi brosis showing only a 4% blasts, the fi nal diagnosis was felt to be more consistent with a chronic myeloproliferative neoplasm, and likely MF. Eventually, the NGS myeloid molecular mutation pro fi le from the bone marrow biopsy aspirate revealed a c.1154_1155insTTGTC (5bpins) CALR mutation in 47.6% cells. No other mutations were detected. The patient met the diagnostic criteria for primary myelo fi brosis.
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Primary myelofibrosis is not primary anymore since the discovery of MPL515 and CALR mutations as driver causes of mono-linear megakaryocytic and dual megakaryocytic granulocytic myeloproliferation and secondary myelofibrosis

Primary myelofibrosis is not primary anymore since the discovery of MPL515 and CALR mutations as driver causes of mono-linear megakaryocytic and dual megakaryocytic granulocytic myeloproliferation and secondary myelofibrosis

Case 1 in table 1 and related igure shows a typical case of primary pre- ibrotic PMF (prePMF) followed by progressive myelo ibrosis, splenomegaly during 20 years follow-up. Sequential bone marrow aspirates and biopsies in 1971 and 1978 showed normal cellularity, no increase of erythropoiesis, selective increase of large megakaryocytes in a bone marrow smears and ine reticulin ibers in a bone marrow biopsy. In 1978, early stage PMF with reticulin ibrosis grade 2 was associated with signi icant splenomegaly but normal platelet counts and no anemia. Since 1985 full blown primary myelo ibrosis (PMF) with progressive anemia and splenomegaly and leuko-erythroblastosis developed and the patient died in 1989 (Table 1). PMF was complicated by a transient episode of erythromelalgic thrombocythemia at platelet counts above 400x10 9 /L at time of progressive PMF during the sequential ibrotic
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Ruxolitinib in myelofibrosis: to be or not to  be an immune disruptor

Ruxolitinib in myelofibrosis: to be or not to be an immune disruptor

Abstract: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm classified according to the 2016 revision of World Health Organization Classification of Tumors and Haematopoietic and Lymphoid Tissue. Ruxolitinib is an oral inhibitor of Janus kinase approved in the USA for the treatment of intermediate or high-risk PMF and approved in Europe for the treatment of splenomegaly and constitutional symptoms of the disease. More recently, case reports described serious opportunistic infections in this neoplasm treated with ruxolitinib. Research studies demonstrated the immunological derangement of this compound mainly based on T, dendritic, and natural killer cell defects. The purpose of this review of the literature was to analyze the relationship among ruxolitinib, immune system and bacterial, viral, fungal, and pro- tozoan infections. A literature search was conducted using PubMed articles published between January 2010 and November 2016. The efficacy of drug in patients with PMF was demonstrated in two phase III studies, Controlled MyeloFibrosis Study with ORal Jak inhibitor Treatment (COMFORT-I and COMFORT-II). Grade 3 and 4 neutropenia were recognized in 7.1% and 2% of patients in the ruxolitinib and placebo arm of COMFORT-I. Grade 3 or 4 neutropenia or leukopenia were observed in 8.9% and 6.3% of ruxolitinib treated patients of 5-year follow-up of COMFORT-II. In addition, leukocyte subpopulations, lymphocyte functions, or antibody deficiency were not documented in either of the studies. The complex interactions between ruxolitinib, bone marrow, immune system, and infections in PMF need further investigation, robust data from a randomized clinical trial, registry, or large case-series.
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Efficacy of ALK5 inhibition in myelofibrosis

Efficacy of ALK5 inhibition in myelofibrosis

Philadelphia-negative myeloproliferative neoplasms (MPNs) comprise multipotent stem cell disorders including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) (1). These disorders are characterized by clonal expansion of myeloid lineage cells due to constitutive activa- tion of the JAK/STAT pathway driven by several somatic mutations in JAK2, MPL, and CALR genes (2–4). Myelofibrosis (MF), either presenting as PMF or evolving from PV or ET secondarily, is exemplified by remodeling of bone marrow stroma towards excessive deposition of extracellular matrix (ECM), neoangio- genesis, and osteosclerosis. These changes collectively result in substitution of normal bone marrow niche proteins and factors with dense fibrillar matrix (5, 6). MF patients suffer from a series of symptoms such as splenomegaly, hepatomegaly, severe anemia, bleeding, and thrombosis caused by bone marrow fibrosis and extramedullary hematopoiesis, which decrease both quality of life and survival. Currently there are limited treatment options for MF, although allogeneic stem cell transplantation provides remissions in younger patients (7, 8). Curative therapies may be lacking, owing, in part, to the poorly understood bone marrow niche–related pathogenesis of MF.
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Successful Control of Acute Myelofibrosis with Lenalidomide

Successful Control of Acute Myelofibrosis with Lenalidomide

Acute myelofibrosis refers to a number of disorders that present with cytopenias, absence of splenomegaly, and a clinical course of fatal peripheral blood insufficiencies or the development of leukemias. A number of disease entities could present with such a picture such as acute panmyelosis with myelofibrosis (APMF), MDS with fibrosis, AML of the M7 subtype, and unspecified myeloproliferative neoplasms with fibrosis. Our patient filled the criteria of APMF as specified in the new WHO listing of hematological neo- plasms [2]; the patient had a typical clinical course, had no morphological abnormalities in the peripheral blood, and no splenomegaly, no megakaryoblasts but an abundant infil- tration of abnormal megakaryocytes (MGK) and reticulin deposition in the bone marrow. According to what has been previously published [3], a prominent feature of APMF that was also present in our patient is the presence of MGK clusters (32% of cases) and microMGK with maturation defects (96% of cases). Of the other disease features, the sole unique abnormality in our patient was an elevated platelet count at presentation that later fell below normal levels and normalized after the 3rd course of lenalidomide. In addition, we could not confirm any other cause of reactive fibrosis since neither digitalis, ACE inhibitors, nor acenocoumarol has been linked to myelofibrosis. The possibility that our patient was an atypical case of a 5q-MDS cannot be supported based on a normal karyotype, lack of dysplastic features in the peripheral, and presence of reticulin fibrosis. However, APMF cases with partial loss of 5q have been observed in one series [7], while aberrations of chromosome 7 were recorded in a significant number of cases usually as part of a complex karyotype. The distinction to the classical primary myelofibrosis (PMF) is relatively straightforward; a brief outline of the major features that characterize APMF, PMF, and the 5q-syndrome are presented in Table 1.
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Emerging treatment options for myelofibrosis: focus on pacritinib

Emerging treatment options for myelofibrosis: focus on pacritinib

Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder that is characterized by ineffective erythropoiesis, abnormal proinflammatory cytokine expression, bone marrow fibrosis, and extramedullary hematopoiesis in organs such as the spleen and the liver. MF, along with polycythemia vera (PV) and essential thrombocythemia (ET), are myeloid malignancies that comprise a subgroup of Philadelphia chromosome- negative myeloproliferative neoplasms. MF can arise de novo as primary myelofibrosis (PMF) or evolve from preexisting PV or ET (post-PV/ET MF). Its pathogenesis is driven by multiple somatic mutations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. Understanding the various genetic mutations linked to MF is an area of active research that may provide prognostic value to guide treatment decisions as well as lead to novel therapeutic targets.
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A Correlative Study on Bone Marrow Angiogenesis with Bone Marrow Fibrosis and Splenomegaly.

A Correlative Study on Bone Marrow Angiogenesis with Bone Marrow Fibrosis and Splenomegaly.

Myelofibrosis is defined as the pathological process characterised by increased deposition of collagen type I and type III.Marrow fibrosis usually results from the stimulation of fibroblast by its growth factors.Fibroplasia is associated with increased blood flow through the marrow substance.Examination of well prepared smears often yields many important informations.The initial primitive hematopoiesis gives rise only to erythroid precursors and macrophages.Fibrosis is not unique to Primary idiopathic myelofibrosis.It occurs in wide variety of diseases including Acute leukemias,Myelomas,Lymphomas and Metastatic deposits especially from breast and prostate.Idiopathic myelofibrosis is characterised by increase in bone marrow reticulin fibrosis and proliferation of blood vessels(Neoangiogenesis – Mean vessel density).The study included total of 25 cases of which eight were cases of primary myelofibrosis.Most of the cases of secondary myelofibrosis were cases of leukemias and lymphomas.IMF was mostly diagnosed in fifth to sixth decade. About 75% of the cases presented with pancytopenia.Increase in marrow cellularity is associated with increase in MVD.Increase in fibrosis is associated with decrease in cellularity.Increase in the spleen size(Extramedullary hematopoiesis) is independent of all the factors.Vascular proliferation is considered to be a mother event in causing splenomegaly and disease progression.
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Myeloproliferative neoplasms (MPNs) are a group of clonal myeloid disorders that affect normal blood cell production in the bone marrow [1-3]. According to the 2016 revision of the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, MPNs are categorized into chronic myeloid leukemia (BCR-ABL1 positive), polycythemia vera (PV), primary myelofibrosis (PMF, prefibrotic/early and overt fibrotic stage), essential thrombocythemia (ET), chronic eosinophilic leukemia (CEL), chronic neutrophilic leukemia

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Incidence of myeloproliferative neoplasms in Calgary, Alberta, Canada

Incidence of myeloproliferative neoplasms in Calgary, Alberta, Canada

The myeloproliferative neoplasms (MPNs) are clonal myeloid malignancies of the bone marrow classified by their unique genetic etiology and hematological histo- morphologic features. The broadest classification is by BCR-ABL (Philadelphia chromosome) positive status for chronic myeloid leukemia (CML). The BCR-ABL negative MPNs, frequently characterized by mutations in Janus kinase 2 (JAK2), are further subclassified into essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), and unclassifiable MPN [1]. Recently, mastocytosis was removed from clas- sification as an MPN and while it has clinical and path- ological features of an MPN, chronic myelomonocytic leukemia has been reclassified as a myelodysplastic syn- drome/MPN disorder. Establishing clear discerning crite- ria between MPN classes requires summation of findings from peripheral blood slides, bone marrow morphology, cytogenetic and genetic alterations, and complete blood
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Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes

Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes

was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, develop- ment of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/ myeloproliferative neoplasm (MPN) syndromes. JAK–STAT inhibitors have changed this, drasti- cally ameliorating symptoms and ultimately beginning to show evidence of impact on survival. Now, the genetic foundations of myelofibrosis and MDS/MPN are rapidly being elucidated and contributing to targeted therapy development. This has been empowered through updated response criteria for MDS/MPN and refined prognostic scoring systems in these diseases. The aim of this article is to summarize concisely the current and rationally designed investigational therapeutics directed at JAK–STAT, hedgehog, PI3K–Akt, bone marrow fibrosis, telomerase, and rogue epigenetic signaling. The revolution in immunotherapy and novel treatments aimed at previously untargeted signaling pathways provides hope for considerable advancement in therapy options for those with chronic myeloid disease.
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Clinical Profile of Philadelphia Negative Myeloproliferative
Neoplasms in India.

Clinical Profile of Philadelphia Negative Myeloproliferative Neoplasms in India.

consist of polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF). Clinical information, from India, on these diseases is limited. We sought to undertake a descriptive study of these disorders with emphasis on the thrombotic complications. Methods: A retrospective chart review of patients who had presented to our institution and had undergone testing for JAK2 mutation analysis was undertaken. Results: A total of 227 patients were analyzed and the most common diagnosis was polycythemia vera, 42%, followed by PMF 21% and ET 13.7%, and 12% of patients had probable MPN. Overall there was a male predominance (78.9%), except in patients with ET. Thrombosis (19.4%) and splenomegaly (11.7%) were the commonest presenting features. Arterial thrombosis was present in 35.77% of patients with probable MPN, 29.9% of PV and 25.8% of ET. Venous thrombosis was present in 17.8% of patients and was most frequent in ET (22.6%). The prevalence of JAK2 positivity was PV 66.7%, ET 58.1% and PMF 47.9%. Hydroxyurea and venesection were the commonest first-line treatment modalities. Most of the patients had at least a partial response to treatment. Conclusions: Polycythemia vera was the commonest MPN and the incidence of thrombosis was
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