|Year : 2014 | Volume
| Issue : 4 | Page : 133-140
Clinical and laboratory presentations of Janus Kinase II-positive patients in Saudi population
H Malhan1, H Alzahrani1, Ghada M Elgohary2, T Owaidah1, M Aslam3, Said Yousuf Mohamed4
1 King Faisal Specialist Hospital, Riyadh, Saudi Arabia
2 Ain Shams University Hospital, Cairo, Egypt
3 King Faisal Specialist Hospital, Jeddah, Saudi Arabia
4 King Faisal Specialist Hospital, Riyadh, Saudi Arabia; Ain Shams University Hospital, Cairo, Egypt
|Date of Web Publication||13-Dec-2014|
Dr. Said Yousuf Mohamed
King Faisal Specialist Hospital, Riyadh, Saudi Arabia. Ain Shams University Hospital, Cairo, Egypt
Source of Support: None, Conflict of Interest: None
Introduction: Janus Kinase II (JAK-II) mutation has a pivotal role in the pathogenesis of the myeloproliferative neoplasms (MPN) and has been shown to be involved in thrombotic complications of these diseases. However, there are limited data regarding clinic-biological features and cytogenetic abnormalities in the Saudi population. Aim: The main aim of this study was to examine clinical presentations, laboratory findings and prognosis of JAK-II-positive Saudi population referred to KFSHRC for testing for variable indications. Methods: A total of 200 patients was referred to our institute for JAK-II mutation testing by polymerase chain reaction based on clinical/laboratory suspicion; about 102 (51%) proved positive. Of the positive cohort, only 62 patients had completed evaluable medical records. Results: Their mean age was 48.2 (range: 16-81) years and 51.6% were males. About 75% had symptoms such as headache 13 [21%]; pruritus 9 [14.5%], visual 7 [11.3%], erythromelalgia 2 [3.2%], and none specific symptoms like fatigue/weakness abdominal discomfort in 30 (48.2%) while the remaining 25% were diagnosed incidentally from abnormal complete blood cells. Clinic-radiological features included: Splenomegaly (53.6%), hepatomegaly (24%), and skin lesions (8%). Thrombosis of portal, hepatic, splenic and mesenteric veins was seen in 24%, stroke and transient ischemic attack in 14%, deep vein thrombosis and pulmonary embolism in 11.2%, ischemic heart disease in 9.6% and 3.2% had arterial thrombosis. The mean peripheral blood count showed white blood cell 13.3 × 109/l, hemoglobin 147.3 g/l and platelets 714 × 109/l. Of the 35 patients evaluated by bone marrow biopsy, the majority (80%) had hyperculluarity. Cytogenetic abnormalities were found in 7 (20%) of the 35 patients and one patient had both JAK-II and BCR/ABL mutations. All the positive patients except 3 (4.8%) were diagnosed as MPNs, 29 (46.7%) polycythemia vera, 24 (38.7%) essential thrombocythemia, 2 (3.2%) primary myelofibrosis and MPN-not otherwise specified in 1 (1.6%). Treatment modalities including hydroxyurea, anagrelide, and thalidomide were used in 75%, antiplatelets were used in nearly 2/3 (61.3%) and 29% of patients required anticoagulants. Three-year actuarial survival was 87% with death related mainly to progressive fibrosis and cytopenia, thrombotic complications necessitating major surgeries, pneumonia or sepsis.
Keywords: Essential thrombocythemia, JAK2 mutation, myeloproliferative neoplasm, polycythemia rubra vera, primary myelofibrosis, thrombosis
|How to cite this article:|
Malhan H, Alzahrani H, Elgohary GM, Owaidah T, Aslam M, Mohamed SY. Clinical and laboratory presentations of Janus Kinase II-positive patients in Saudi population. J Appl Hematol 2014;5:133-40
|How to cite this URL:|
Malhan H, Alzahrani H, Elgohary GM, Owaidah T, Aslam M, Mohamed SY. Clinical and laboratory presentations of Janus Kinase II-positive patients in Saudi population. J Appl Hematol [serial online] 2014 [cited 2021 Sep 25];5:133-40. Available from: https://www.jahjournal.org/text.asp?2014/5/4/133/146947
| Introduction|| |
Myeloproliferative neoplasms (MPNs) are a group of diseases characterized by clonal expansion of an abnormal hematopoietic stem/progenitor cell, and are classified by the predominant myeloid element involved in the disease process. They include chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia rubra vera (PRV), and idiopathic myelofibrosis (IMF), as well as chronic eosinophilic leukemia/hypereosinophilic syndrome, chronic myelomonocytic leukemia, chronic neutrophilic leukemia and systemic mastocytosis.  Their natural history is marked by thrombotic and hemorrhagic complications and a propensity to transform into myelofibrosis and acute leukemia.
New development in the molecular genetics has remarkably improved diagnosis, differential diagnosis as well as our understanding of the pathogenesis of such diseases particularly after wide use of JAK2 recurrent mutational abnormalities. V617F mutation in JAK2 exon 14, which involves 95% of polycythemia vera (PV) and 60-70% of ET and primary myelofibrosi (PMF) patients. ,
Janus Kinase II is a cytoplasmic tyrosine kinase with a key role in signal transduction from multiple hematopoietic growth factor receptors.  Recently, a gain-of-function mutation was identified in the JAK2 gene, which results in a valine-to-phenyalanine substitution at position 617 (V617F). ,, Sensitive methods have demonstrated the presence of the JAK2 mutation in >95% of patients with PRV and in 60% of patients with ET or IMF. , The mutation is somatic and occurs at the level of a hematopoietic stem/progenitor cell. In all studies till date, the mutated JAK2 has been found in myeloid cells such as bone marrow cells, granulocytes, platelets and erythroblasts derived from CD34 + cells, but not in T-cells. In addition, it was found in hematopoietic colonies derived from hematopoietic progenitor cells. In contrast, the mutation was not present in non-hematopoietic cells. 
The JAK2 mutation is an acquired dominant process that leads to persistent proliferation of hematopoietic progenitor cells with diminished apoptosis leading to different clinical manifestations associated with an increase in the number of platelets, red blood cells and white blood cells (WBCs) in variable combinations.  JAK2 mutation probably also increases the risk of thrombotic events. ,,
Hereby, we describe a retrospective study of JAK-II positive patients, both with and without hematological features of MPNs in a Saudi population.
| Methods|| |
This was a retrospective study of patients who tested for JAK-II at our institute between January 1 st , 2008 and December 31 st , 2009. Patients were eligible for inclusion in the study if they tested positive for JAK-II and followed-up at our institute as shown in [Figure 1]. Medical charts were reviewed to collect various demographic, clinical presentation, laboratory findings, complications and treatment modalities.
|Figure 1: Flow sheet of Janus Kinase II testing results as referred to the laboratory from the clinical services|
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JAK 2 mutation was tested using real-time polymerase chain reaction (RT-PCR) and Direct Sequence Analysis. Total nucleic acids were isolated from peripheral blood cells by the NucliSens extraction kit (bioMerieux Inc., Durham, NC) according to the manufacturer's instructions, first strand cDNAs were then prepared by reverse transcription of total RNAs with random primers at 55°C for 30 min, followed by PCR reactions using Super-Sript III one-step RT-PCR system with platinum TaqDNA polymerase (Invitrogen, Carlsbad, CA). For the amplification of JAK2 exons 12 through 15, the following primer set and conditions according to previously reported were used.  Sequence data were then base-called, assembled, and analyzed by ABI Prism SeqScape software (Applied Biosystems) using the JAK2 sequence.
Data analysis was performed in SPSS version 20. Descriptive analysis was used to assess the frequency of disease entities, bio-clinical and laboratory findings. Actuarial overall survival, transformation risk, and complications were explored. Statistical significance was set at a P < 0.05 level.
| Results|| |
During the 2 years study period (2008-2009), 200 patients were tested for the presence of a JAK-II mutation and 102 had positive test results. Out of these, 62 patients fulfilled the inclusion criteria and enrolled into this study. The excluded patients were mainly referred from other centers for only testing for JAK-II with no clinical data. There was an approximate equal split between male and female patients with 34 (51.6%) male patients. The mean age of the study cohort was 48.40 with age range 16-81 years.
According to WHO new classification, the following were the clinical categories presented in the cohort: 29 patients (46.7%) were diagnosed with PRV, 24 (38.7%) ET and 2 (3.2%) patients with PMF, 1 patient with MPN in transformation into acute leukemia, 1 patient had a diagnosis of undefined-MPN [Table 1]. There were 6 (10%) patients presenting with hepatic venous thrombosis ( Budd-Chiari syndrome More Details [BCS]) with hepatomegaly, splenomegaly, normal or high platelet count with other features suspicious of MPN with JAK-II positivity but it was difficult to designate them to specific WHO-MPN category because splenomegaly can occur primarily in uncomplicated PV, PMF or with ET complicated by BCS. Moreover, hematocrit and hemoglobin (Hb) can falsely decrease in PV patients when they develop BCS either due to gut bleeding or due to dilutional effect secondary to secondary overproduction of plasma. Overall, 46 (74%) patients were symptomatic and had variable clinical presentations including headache in 13 patients (21%), pruritus in 9 patients (14.5%), visual symptoms in 7 patients (11.3%), and erythromelalgia in 2 patients (3.2%). Nonspecific symptoms were observed in 30 patients (48.4%), including abdominal discomfort, arthralgia, and the generalized fatigability. Splenomegaly was observed in 33 patients (53.6%), hepatomegaly in 15 patients (24%) and 5 patients (8%) had skin lesions.
|Table 1: Summary of symptomatic presentations and clinical observations of patients with JAK-2 positive MPNs (n:62)|
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A protean of thrombotic complications was observed: Splanchnic thrombosis was the most common in 15 (24%) patients (portal vein, splenic vein and mesenteric vein) followed by arterial thrombosis (n: 11; 18%) some have > 1 type) and 7 (11%) patients had BCS. One patient had extensive intra-abdominal venous thrombosis with a diagnosis of non-MPN that required splenectomy, laparotomy, and bowel resection, resulting in short bowel syndrome and >1 type of anticoagulation intervention. Lower limb arterial thrombosis was observed in 2 patients (3.2%), sagittal and dural sinuses thrombosis were observed in 3 patients (4.8%). Ischemic heart disease was found in 6 patients (9.6%) and stroke/transient ischemic attack in 9 patients (14.5%). Bleeding episodes were only noted in 3 patients (4.8%) and were related to dental, and menstrual bleeding (BCS) was identified in 7 patients (11.2%); in 1 of these there was no clear manifestation of MPN, in 3 patients BCS was associated with PRV and in the other 3 patients it was associated with ET. Two (3.2%) patients were diagnosed as undefined MPN and 1 (1.6%) patients were diagnosed as non-MPN, one of whom had bowel ischemia without hematological manifestation of MPN. Only one patient (1.6%) developed leukemic transformation, and 1 patient (1.6%) had thrombocythemia variant of CML with positive Philadelphia chromosome according to fluorescent in situ hybridization (FISH) and molecular tests.
Many laboratory changes were observed [Table 2]. About 23/62 (37%) had WBC above 10,000 and 9 (15%) patients had counts above 15 and 5 (8%) had a count > 25,000/ul, 25 (40%) had a Hct > 0.5 while 17 (27) % had Hct > 0.55, and 5 (8) had 0.6 Hct or more.
|Table 2: Relevant abnormalities for JAK2 positive patients with MPN who had evaluable bone marrow biopsies (n:62)|
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Bone marrow biopsies were performed in only 35 patients with mean cellularity was 77.8%. Bone marrow fibrosis was assessed in only 14 patients; increased fibrosis had been seen in 9 patients. Megakaryocytes were increased in 31 (89%) patients and Iron levels were found to be, decreased in 22 (63%) patients and increased only in 5. Abnormal cytogenetic was observed in 7 (20%) of the 35 tested patients [Table 3]. Of the 21 patients tested for BCR-ABL using FISH, only one patient had a positive BCR-ABL result.
|Table 3: Cytogenetic abnormalities for JAK2 positive patients with MPN who had evaluable bone marrow biopsies (n:35)|
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During the follow-up period, patients underwent various surgical interventions [Table 4]. These included: 3 underwent liver transplantation, 4 transjugular intrahepatic portosystemic shunt (TIPSS) procedures, 2 inferior vena cava filter placement, 1 embolectomy, 1 splenic irradiation, 1 intestinal resection, 1 nephrectomy and 1 splenectomy.
|Table 4: Surgical interventions in patients with JAK2 positive MPN (n:62)|
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The majority of patients (77%) received specific disease targeted treatments. The most common therapy used was hydroxyurea in 72.6% of patients. About 11 patients were using hydroxyurea in combination with at least one other agent, including 6 patients who were also using Anagralide, one using α-interferon, one using both Anagralide and α-interferon, and one using imatinib who had positive BCR-ABL. Other agents used in less frequency included thalidomide, prednisone and/or anabolic steroids. Most of them also received additive treatments (76%) most commonly, aspirin (50%) or venesection (10%) or the two in combination (13%). Other additive treatments used were plavix (8.1%) and dipyridamole (3.2%). Anticoagulation therapy was required in 29% of patients with 19.4% continuing on anticoagulation until the final follow-up.
Over 3 years follow-up, a total of 8 patients died (actuarial survival = 87%) [Figure 2]. Causes of death were: Sepsis in three patients, pneumonia in 3 patients, and metastatic renal carcinoma in 1 patient and was undocumented in the final patient. Leukemoid transformation was observed in 1 patient (1.6%) and myelofibrotic transformation in 5 patients (8.1%). Patients who were alive at the last follow-up had significantly lower absolute neutrophil counts, platelets and alanine transaminase (ALT) levels compared to those who died during the study period [Table 5].
|Figure 2: Actuarial survival of patients with Janus Kinase II positive mutation at KFSHRC (n: 62)|
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|Table 5: Comparison of laboratory findings in patients who were alive at the last follow-up with those who died (8;13%) during the study period|
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| Discussion|| |
To our knowledge, this is the first study of JAK-II positive patients in Saudi Arabia. Various clinical and laboratory findings were reviewed retrospectively.
We found a significant number of patients who were asymptomatic and had an incidental discovery of positive JAK-II after abnormal complete blood cells counts (n = 14; 25%) as compared to international findings.  The nature of presentations probably reflects the nature of the referral from other institutions as peripheral or local hospitals tend to refer more advanced, symptomatic or complicated patients. It may also reflect the allele burden of JAK2.  The relatively younger age compared to the international community may simply reflect the younger age of the Saudi population or the logistics of referral as KFSHRC is a transplant center and usually accepts relatively younger patients who may benefit from transplantation when needed and the general societal trend for better mobilization and travel of younger patients compared to elderly especially when they become sick or comorbid.
Over half of the patients had splenomegaly, and a third of patients had hepatomegaly, and most of these patients with the majority been diagnosed as PRV.  However, some patients with polycythemia may have splenomegaly and other criteria of PV (low Erythropoietin (EPO), bone marrow findings) without elevated Hct or Hb may reflect the occurrence of associated iron deficiency or splanchnic venous thrombosis, which is associated with increased plasma formation or occurrence of concurrent gastrointestinal (GI) bleeding causing drop of Hb and Hct and false absence of high hematocrit, a phenomenon better called Inapparent polycythemia. 
Thrombotic complications were prevalent, occurring in over half of the patients (52%).
Although such a high rate may reflect the nature of the referral with the tendency in referring "complicated" cases of MPN. It may also reflect the delayed diagnosis due to the relatively chronic indolent nature of their hematological changes associated with early disease and the more acute nature when they present with thrombotic complication. For this reason, there should be a low threshold for diagnosis and early risk stratification to help prevent such life threatening complications from happening if not diagnosed early, or if a form of antithrombotic treatment is not initiated promptly. This represents an unmet need for MPN patients and a real challenge to health care systems in the country, like Saudi Arabia, where medical care is developing so rapidly. Initiation of registries and mass awareness as well as epidemiologic research in may help to achieve such goals.
The observation that those who had venous did not have arterial thrombosis and vice versa probably relates to the fact that once thrombosis of any nature was diagnosed, anticoagulant treatment was initiated with or without cytoreductive therapy. Such prompt treatment was effective in preventing other forms of thrombosis whether arterial or venous.
When low-dose Aspirin was used in the largest European study in PV European collaboration study on low-dose aspirin in polycythemia (ECLAP), cardiovascular mortality although accounted for 41% of deaths, death rate was only 1.5 deaths per 100 persons per year and the cumulative rate of nonfatal thrombosis was 3.8 events per 100 persons per year, without a difference between arterial and venous thrombosis. 
In ET prospective studies, the rate of fatal and nonfatal thrombotic events ranged from 2% to 4% patient years; , however, arterial events was more frequent than venous thrombosis ,, highlighting the pivotal role of JAK-II and the associated blood cellular and acellular prohtrombotic status of such patients. In the pathogenesis of thrombosis in such diseases and the importance of early detection and assessment and stratification for thrombotic risk so that antiplatelets, anticoagulants and hydroxyurea or other relevant modalities would be instituted earlier.
Splanchnic vein thrombosis in either the portal vein, splenic vein or mesenteric vein was the most common type of thrombosis observed, accounting for thrombotic events in 14 patients and was predominantly observed in PRV patients, with a smaller observed in patients with a diagnosis of ET. In a large study of BCS in 1062 patients, the prevalence of MPN was 40.9% and in 855 patients with portal vein thrombosis was 31.5% only.  A recent study from the region  did report very low incidence of MPN compared to factor V Leiden (FVL) mutation or methyl tetrahydrofolate reductase polymorphism in BCS and portal vein thrombosis. This was probably related to a selection bias as patients were referred first to hepatology and liver transplant service when some degree of liver failure occurred, which masked many of the peripheral findings of MPN like high platelet count and high WBC or hematocrit. Meanwhile, it is well known that FVL and MTHFR polymorphisms are prevalent in such Caucasian population.
In our study, splanchnic thrombosis were significantly (74%; P < 0.05) associated with elevated lactic dehydrogenase level (>260 u), high WBCs and organomegaly. Because, many, especially BCS, can be life threatening recurrent even after intervention,  they need multidisciplinary care especially, hepatology, interventional radiology for TIPSS or stenting, liver transplantation and hematology with special expertise in MPN and thrombosis.
Special attention should also be paid to the monitoring of anticoagulants in such patients as they may have tendencies to bleed due to concomitant liver affection, portal hypertension or esophageal-gastric varices or just portal gastropathy or low platelet count in late phases of the disease.
The relatively lower rate of bleeding with anticoagulant use in such difficult patients suggests that close monitoring and better selection of type of anticoagulant may be all what MPN patients need to benefit from such an important modality.
Lower limb arterial thrombosis was less commonly observed, in only 3.2% of patients, whilst lower extremities' deep vein thrombosis (DVT) and pulmonary embolism occurred in 11.2% of patients. Such a relatively lower risk of DVT may be partly explained by the relatively younger age of the referred patients which would be expected to be associated with better mobilization as the risk of thrombosis is usually cumulative and may be associated with multiple factors.  Nonetheless, such a rate and risk in our study population appear to be in line with that reported in previous studies of JAK-II-positive patients. , However, there is still considerable controversy in the literature with respect to the association between JAK-II mutation and risk of thrombosis in MPN patients. A number of studies have demonstrated an independent association between the JAK-II mutation and thrombotic events ,,,,, with a reported hazard ratio (HR) in one study as low as 3.97 (95% confidence interval 1.34-11.7 (P = 0.0013) compared to JAK-II wild-type patients (HR = 1.0)  However, other studies have failed to demonstrate an increased risk of lower limb thrombosis in ,,, A recent study in Egypt examined the contribution of JAK-II mutation in 106 patients presenting with their first episode of DVT and only 6 patients (5.7%) were found to have a positive JAK-II result; with no statistically significant relationship between the presence of JAK-II and VTE. 
In our study, bleeding was noted in 4.8% of patients, the majority of whom had a diagnosis of PRV we had one incidence of GI bleeding, in a patient who presented with splanchnic thrombosis, indicating the likely cause of bleeding in this patient. Other bleeding sites were mainly dental and menstrual. These findings are comparable to previous reports of bleeding prevalence of 3-18% in ET patients and 3-8.1% in PRV patients  Such incidence does not preclude the potential for GI bleeding especially those complicated by Budd-Chiari causing liver cell failure and portal hypertension, congestive gastropathy. However, the relatively low incidence of GI bleeding even in those with portal vein, mesenteric vein and hepatic vein thrombosis may reflect the heightened pro-thrombotic tendency which gives such patients an additional advantage preventing frequent or serious bleeding.
On the contrary, they tend to re-thrombose as shown in many studies of TIPS placement for those with BCS.  Such findings are probably related the underlying sticky platelet syndrome, up-regulated adhesion molecule on both platelets and endothelium and increased pro-coagulants. 
The relatively low rate of abnormalities may reflect the usually low yield of cytogenetics in such disorders. Nevertheless, 9p-has been reported in PV. ,
There were limitations to this study. As in any retrospective analysis, we were only able to use data contained in medical notes. Consequently, there was missing data, particularly for laboratory findings where a complete set of analyses may not be performed. In addition, only patients who were JAK-II positive were included in this analysis, therefore, we were unable to draw any conclusions about the impact of JAK-II mutation on thrombotic complications.
We have noticed only 1 patient had positive BCR-ABL test who responded to treatment with imatinib, it's rare to find combination of both JAK-II mutation and BCR-ABL fusion gene, for that reason the WHO currently has no recommendations on how to best classify these MPN.  Generally, these patients are given some variation of the diagnosis BCR-ABL and JAK-II positive MPN. Leukemoid transformation occur in MPN secondary to multiple factors, include circulating blast at time of diagnosis, platelet count, acquisition of other mutation like TET2, and therapy related effects, in our study only one patient transformed to acute myeloid leukemia, in compare to one study for PMF patients who had 3.9% transformation. ,
Our study has some important limitation including, but not limited to,: The none-population based nature of the study, the use of the PCR targeting only exon-14 which diagnose only 92% of PV, around 50% of ET and 50-60% of PMF and the retrospective nature of the study as well as the short duration of follow-up which makes assessment of important parameters like, OS and transformation very difficult. Also, cytogenetic testing and molecular genetic panel should have been more inclusive and done for a larger number of patients in the future as cytogenetics and molecular assessment were shown to improve in risk assessment and stratification especially in PMF. Also, the degree of fibrosis should be more standardized and validated for future reference as it may help in prognostication.  Moreover; it was beyond the scope of this study to assess other conventional cardiovascular risk factors like hypertension, hyperlipidemia, diabetes and smoking history which had been shown in some studies to increase the risk of thrombosis. 
In summary, this is the first study to examine the phenotype of JAK-II-positive patients in Saudi Arabia. In our JAK-II-positive population, we found that the patient presented with a variety of symptoms and over the follow-up period experienced significant complications that required major interventions and was the cause of considerable mortality.
Most thrombotic events occur early and can be prior to establish the diagnosis of MPN  as patients with MPN who are enrolled on different antiplatelet, anticoagulants or cytoreductive therapy after diagnosis would have relatively low incidence of thrombosis and mortality due to thrombosis. The pathogenesis of thrombosis in classic MPNs is multifactorial; rheologic abnormalities due to increased red cell mass in PRV, abnormal function of platelets and their enhanced interaction with leukocytes and endothelial cells, are all possible contributing factors; however, neither thrombocytosis nor increased hematocrit (at least until 52%) are clearly associated with occurrence of thrombosis. 
The observation that patients who died during over 3 years follow-up period had a hyperproliferative nature (median WBCs around 17,000/ul, median platelet count >1 million) matches other studies and general consensus regarding high risk PV, ET and myelofibrosis. ,,, Moreover, higher ALT/aspartate aminotransferase is a reflection of thrombosis of hepatic and/or portal circulation or liver affection and clearly indicates the significant impact of uncontrolled myeloid elements on disease prognosis and mandates prompt treatment to avoid such poor outcome. It may also suggest that liver affection carries significantly poor prognosis (P ≤ 0.001) whether due to hepatic venous thrombosis or fibrosis and is associated with high mortality and every single effort should be done to avoid such an outcome.
Transformation to postpolycythemic or postthrombocythemic myelofibrosis represents the natural evolution of PRV and ET, occurring late in the clinical course and at relatively low rates. The estimated 15 years risk for transformation following diagnosis of PRV is 5% only.  There is a paucity of data in ET, although studies have suggested the rate to be lower than that for PV, at 0.7%.
Leukemic transformation, or blast phase, occurs in approximately 15% of PMF patients and in <10% of PRV and ET patients 37 by unknown mechanisms, and chemotherapy may increase the risk of LT, ,,, in addition to evolution of different genetic mutations, such as IDH1/2, AML1/RUNX1, and TET2 and TP53.
| Conclusion|| |
This is the first largest study about JAK2 positive MPN cases diagnosed over 2 years at a single center with follow-up for 3 years showing protean presentations with prevalent arterial and splanchnic venous thrombosis and needed many multidisciplinary interventions including liver transplantation and TIPPS. To avoid late presentations, improve survival and quality of life, many unmet needs should be satisfied including initiation of registry, improving awareness, early stratification, applying guidelines and early referral.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]