scholarly journals JAK2 GGCC (46/1) Haplotype in Unprovoked Venous Thrombotic Events

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4258-4258
Author(s):  
Maged Al-Ammari ◽  
Abdul Ali Peer Zada ◽  
Ibraheem H. Motabi ◽  
Belal M. Albtoosh ◽  
Syed Y. Altaf ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Tertiary Care ◽  
Jak2 V617f ◽  
The Other ◽  
Healthy Population ◽  
Cerebral Vein ◽  
Splanchnic Vein Thrombosis ◽  
Vein Thrombosis

Abstract Background: JAK2 GGCC 46/1 haplotype can be represented by four main SNPs (rs3780367, rs10974944, rs12343867, and rs1159782) which replace one cytosine and three thymidines by two guanosines and two cytosines, generating a "GGCC" combination. These four SNPs located on JAK2 introns 10, 12, 14, and 15, respectively, and are always inherited together, being in complete linkage disequilibrium. The 46/1 component of the name came from Jones et al. study where the haplotype structure of the JAK2 gene was mapped using 14 SNPs genotyped by the Wellcome Trust Case Control Consortium (WTCCC) in 1500 healthy blood donors. Two haplotypes (numbers 46 and 1) were found to be identical except for one SNP, and they have a combined frequency of 0.24 in healthy individuals. Numerous observational studies associate this haplotype with myeloproliferative neoplasms (MPNs), as well as splanchnic vein thrombosis (SVT) and non-splanchnic vein thrombosis (non-SVT). In contrast to 24% frequency noted in healthy population, the frequency goes up to 40-80% in JAK2 V617F mutated MPN, and in 64% of those with JAK2 exon 12 mutations (Anelli et al. IJMS, 2018). We herein report our study of JAK2 GGCC (46/1) Haplotype in unprovoked Venous Thrombotic Events (VTE) in patients with negative thrombophilia workup, including negative JAK2 V617F mutation. Methods: We retrospectively identified patients positive for one of the two SNPs (rs12343867 and rs10974900) and unprovoked venous thrombotic among adult patients with negative thrombophilia workup (including JAK2 mutation) treated at tertiary care center from January 2018 to January 2021. Results: We have identified 8 patients, Table (1), that were positive for JAK2 46/1 haplotype SNPs, of whom 62.5% were homozygous 2/2, 25% heterozygous 1/2, while only 12.5% harbor homozygous 1/1 (a normal variant of JAK2 haplotype). The median age 48.5 years (23-65), and the majority (87.5%) were females. Thrombosis site was noted to be SVT in half of the patients, while non-SVT was noted in the other half (12.5% had cerebral vein thrombosis, 12.5% had deep venous thrombosis, 12.5% had a pulmonary embolism, and 12.5% had jugular vein thrombosis). Half of the patients had more than one site venous thrombosis and the other half had only one site. Around 37.50% of the patients had recurrent venous thrombosis on top of therapeutic anticoagulation. Two patients (25%) had high hemoglobin (17.4/16.7) g/dl, but did not fulfill the criteria for polycythemia vera diagnosis (of whom one is a male smoker and one was a female). None of the patients had leukocytosis or thrombocytosis. By imaging, one patient had mild splenomegaly which could be related to SVT. Conclusion: We report on a potential correlation between unprovoked thrombotic events, mainly venous thrombotic events, with JAK2 46/1 haplotype in patients with a negative thrombophilia workup, a finding that merit further investigation. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Splanchnic vein thrombosis in myeloproliferative neoplasms: pathophysiology and molecular mechanisms of disease

2016 ◽  
Vol 8 (3) ◽  
pp. 107-118 ◽  
Author(s):  
Joan How ◽  
Amy Zhou ◽  
Stephen T. Oh
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Blood Cells ◽  
Molecular Mechanisms ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Splanchnic Vein Thrombosis ◽  
Vein Thrombosis ◽  
Disease Mechanisms ◽  
Younger Age

Myeloproliferative neoplasms (MPNs) are the most common underlying prothrombotic disorder found in patients with splanchnic vein thrombosis (SVT). Clinical risk factors for MPN-associated SVTs include younger age, female sex, concomitant hypercoagulable disorders, and the JAK2 V617F mutation. These risk factors are distinct from those associated with arterial or deep venous thrombosis (DVT) in MPN patients, suggesting disparate disease mechanisms. The pathophysiology of SVT is thought to derive from local interactions between activated blood cells and the unique splanchnic endothelial environment. Other mutations commonly found in MPNs, including CALR and MPL, are rare in MPN-associated SVT. The purpose of this article is to review the clinical and molecular risk factors for MPN-associated SVT, with particular focus on the possible mechanisms of SVT formation in MPN patients.

Incidence of Arterial and Venous Thrombosis in Vonwillebrand Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 101-101
Author(s):  
Syed Hassan ◽  
Waqas Qureshi ◽  
Syed Amer ◽  
Mohamed Almahmoud ◽  
Vrushali S. Dabak ◽  
...  
Keyword(s):  
Portal Vein ◽  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Conflicts Of Interest ◽  
Conditional Logistic Regression ◽  
Control Sample ◽  
Cerebral Vein ◽  
Vein Thrombosis ◽  
Hospital Database ◽  
Q Wave

Abstract Abstract 101 Objective: To date, only a few case studies have reported occurrence of thrombosis in patients with VonWillebrand disease (VWD). No studies have looked at its incidence in this patient population. The aim of this study was to test our hypothesis that decreased VonWillebrand factor (VWF) levels confer a protective effect on arterial and venous thrombosis. Methods: This is a retrospective cohort study including patients (n = 350) with the ICD-9 code of VonWillebrand disease who were identified from our hospital database over a period of 25 years (Jan 1985 – Dec 2010). An extensive review of the patients' medical records was carried out to authenticate VonWillebrand disease, after which 198 patients were included in the analysis. A random parallel control sample without VonWillebrand disease matched for age, sex, hypertension, hyperlipidemia, atrial fibrillation and diabetes mellitus was also obtained from the hospital database. The primary outcomes were incidence of diagnosis of symptomatic arterial thrombosis [Cardiovascular events (CAD): Unstable angina, Q wave and non Q wave Myocardial infarction; Cerebrovascular events (CVD): stroke and transient ischemic attack] and venous thrombosis [deep vein (DVT), cerebral vein, portal vein, renal vein thrombosis and pulmonary embolism (PE)]. The results were computed using multivariate conditional logistic regression analysis and proportions were compared using McNemer'sChi – square test. Results: Out of 198 patients (mean age 44.2 ± 17.5, women 72%) with VWD, the incidence of arterial and venous thrombosis is reported in table 1.VWD was found to be an independent protective predictor from arterial thrombosis (OR 0.28, 95% CI 0.14 – 0.54, p <0.0001), more so in CAD (OR 0.28, 95% CI 0.12 – 0.64, p = 0.002) than in CVD (OR 0.28, 95% CI 0.10 – 0.77, p = 0.01). However this was not the case in venous thrombosis as seen in DVT (OR 0.62, 95% CI 0.20 – 1.93, p = 0.41) or PE (OR 0.50, 95% CI 0.09 – 2.75, p = 0.423).One case of portal vein thrombosis was also seen. Also the arterial thrombosis in VWD was not a predictor of mortality; 10 deaths were reported in VWD patients, while 4 in control population (OR 1.8, 95% CI 0.49 – 6.76, p = 0.37). Conclusion: In a population of relatively younger individuals with VonWillebrand disease, our study suggests a reduced incidence of arterial thrombosis but not in venous thrombosis. This brings up the possibility that there are could be other pathways or factors involved in arterial and venous thrombosis. To our knowledge, this is the first large observational study that has provided insight into the thrombotic disease in this group of patients. Disclosures: No relevant conflicts of interest to declare.

Lack of Association Between the 46/1 JAK2 Haplotype and the Presence of JAK2V617F Mutation In Splanchnic Vein Thrombosis Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4120-4120
Author(s):  
Eirini G Kouroupi ◽  
Bruno Cassinat ◽  
Aurelie Plessier ◽  
Sylvia Bellucci ◽  
Christine Chomienne ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Jak2v617f Mutation ◽  
Fisher Exact Test ◽  
Peripheral Vein ◽  
Splanchnic Vein Thrombosis ◽  
Vein Thrombosis ◽  
Tag Snp ◽  
Mutational Status ◽  
The Impact

Abstract Abstract 4120 Aim: The majority of myeloproliferative neoplasms (MPN), i.e. Polycythemia vera (PV), Essential Thrombocytemia (ET) and Primary Myelofibrosis, are characterized by the presence of the acquired JAK2V617F gene mutation. Recent studies revealed that the 46/1 or “GGCC” haplotype located in the JAK2 gene is strongly associated with the development of a JAK2V617F positive MPN. However, this particular haplotype was also detected in excess in JAK2V617F negative MPN carrying mutations across JAK2 exon 12 or the MPL gene, suggesting that this germline genetic variation increases the risk of developing a MPN regardless of the acquisition of one particular mutation. A MPN is found in approximately half of the patients presenting with Splanchnic Vein Thrombosis (SVT) and JAK2V617F mutation is present in virtually all of these MPN patients. In this study we sought to clarify the impact of the JAK2 46/1 haplotype on the susceptibility to SVT. Patients and Methods: Peripheral blood was obtained after informed consent; following DNA extraction we proceeded to genotyping using commercially available TaqMan SNP genotyping assays for one tag SNP (rs10974944) which is in complete linkage disequilibrium with the 46/1 haplotype. Results were confirmed using another tag SNP (rs1234867). The study was performed on 170 patients with SVT, 58 patients with peripheral vein thrombosis and 31 patients with JAK2V617F positive PV. Results: In the 170 patients with SVT the frequency of G-allele that stands for the 46/1 haplotype was 0.28 (CC n=89; C/G n=67; G/G n=14), not significantly different from that of the published population controls (n=1500) from the Welcome Trust Case Control Consortium WTCCC (0.24; p=0.11 by the Fisher exact test). The frequency of the 46/1 haplotype in 58 patients with peripheral vein thrombosis was also similar to that of the WTCCC (0.24). However, the frequency of the 46/1 haplotype in SVT patients was significantly different from its frequency in a group of 31 patients with JAK2V617F positive PV (0.52; p=0.0005). When we analysed SVT patients according to their JAK2 mutational status, we found no difference in the frequency of the 46/1 haplotype between the JAK2V617F positive patients (0.27; n=75) and the JAK2V617F negative patients (0.28; n=95) (p=0.90). Of note, a JAK2 allele burden greater than 50% was observed in 11% of patients with JAK2V617F positive SVT and 45% of patients with JAK2V617F positive PV. Conclusions: In this large cohort of 170 patients with SVT the frequency of the 46/1 haplotype was not different from the cohort of controls of the WTCCC. This result suggests that the 46/1 haplotype is not a susceptibility locus for the development of SVT. Moreover, this haplotype was not overrepresented in the group of SVT patients harbouring a JAK2V617F mutation compared to JAK2V617F negative patients. This result is in apparent contradiction with the hypothesis that the 46/1 haplotype predisposes to the acquisition of JAK2V617F mutation or of a MPN, in agreement with recent studies reporting almost identical 46/1 frequencies between V617F-negative patients and V617F-positive patients with low mutation burden (i.e. <50%), which is the case of SVT patients in this series. Disclosures: No relevant conflicts of interest to declare.

Cerebral Vein Thrombosis In Patients With Myeloproliferative Neoplasms

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4068-4068
Author(s):  
Ida Martinelli ◽  
Valerio De Stefano ◽  
Alessandra Carobbio ◽  
Maria Luigia Randi ◽  
Claudia Santarossa ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Myeloproliferative Neoplasms ◽  
Similar Proportion ◽  
Cerebral Vein ◽  
Recurrent Thrombosis ◽  
Antithrombotic Treatment ◽  
Cerebral Vein Thrombosis ◽  
Vein Thrombosis ◽  
Essential Thrombocytemia

Abstract Background Patients with Philadelphia-negative myeloproliferative neoplasms (MPN) can develop venous thrombosis and MPN are the leading cause of splanchnic vein thrombosis. Cerebral vein thrombosis (CVT) is a rare life-threatening disease that in approximately 3% of cases encounters MPN among risk factors and tends to recur in 2-4% of patients as CVT and in 4-7% as venous thrombosis at other sites. Little or no information is available on patients with MPN who develop CVT. Objective and design To investigate the characteristics and clinical course of CVT in patients with MPN we carried out a multicenter (n=11), observational, retrospective cohort study. Patients Centers were asked to provide information on index patients with MPN who developed CVT (group MPN-CVT). For each of them, 2 patients with MPN and venous thrombosis other than CVT (group MPN-VT) and 4 patients with MPN and no venous thrombosis (group MPN-NoVT) were provided, matched by sex, age at diagnosis of MPN (+/-5 years) and type of MPN (polycytemia vera, essential thrombocytemia, myelofibrosis) with index patients. Results From January 1982 to June 2013, 48 MPN-CVT, 87 MPN-VT and 178 MPN-NoVT patients were identified in a population of 5,500 patients with MPN. Diagnosis of MPN and thrombosis coincided in 46% of MPN-CVT and 29% of MPN-VT patients (p=0.046). Compared to MPN-NoVT, MPN-CVT and MPN-VT patients had a higher prevalence of thrombophilia abnormalities (40% and 35% vs 21%, p=0.015) and, among those with essential thrombocytemia, of the JAK2 V617F mutation (76% and 78% vs 55%, p=0.059). Compared to MPN-VT, MPN-CVT patients had a higher rate of recurrent thrombosis (42% vs 25%, p=0.049) that in two-third of patients in both groups was venous, with a similar site distribution. This difference occurred despite a shorter median follow-up period (6.1 vs 10.3 years, p=0.019), a higher proportion of patients on long-term antithrombotic treatment (94% vs 84%, p=0.099) and a similar proportion of patients on cytoreductive treatment (75% vs 72%, p=0.745) among MPN-CVT than MPN-VT patients. The incidence of recurrent thrombosis was 8.8% patients/year in MPN-CVT and 4.2% patients/year in MPN-VT patients (log-rank test, p=0.022) and CVT was the only variable in a multivariate model including blood counts, thrombophilia, cytoreductive and antithrombotic treatment, that was predictive of recurrent thrombosis (HR 1.86, 95%CI 1.00-3.58). Conclusions Patients with MPN develop recurrent thrombosis in a much higher proportion than those without, particularly if they had a CVT. Patients with MPN and CVT have an approximately 2-fold increased probability to develop recurrent thrombosis than those with MPN and venous thrombosis at other sites, independently of other risk factors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals JAK-2-Positive Latent Myeloproliferative Neoplasms with Splanchnic Vein Thrombosis- from the Hematopathology Perspective

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5381-5381
Author(s):  
Dina Sameh Soliman ◽  
Aliaa Amer ◽  
Firyal Ibrahim ◽  
Ahmad Al-Sabbagh ◽  
Halima El-Omri ◽  
...  
Keyword(s):  
Portal Vein ◽  
Venous Thrombosis ◽  
Diagnostic Criteria ◽  
Myeloproliferative Neoplasms ◽  
Splenic Vein ◽  
Splenic Vein Thrombosis ◽  
Splanchnic Vein Thrombosis ◽  
Vein Thrombosis ◽  
Pathologic Features

Introduction: Philadephia-negative Myeloproliferative neoplasms (MPNs) include polycythemia Vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The diagnosis of MPNs and further sub classification are based mainly on WHO diagnostic criteria which rely on the presence of an evidence of single or multiple cell lineage proliferation reflected by elevated hemoglobin, and / leukocytosis and /thrombocytosis. In addition, to presence of certain pathologic features in the bone marrow (BM) including hypercellularity , panmyelosis, proliferation of megakaryocytes, the presence of atypical megakaryocytes and or increased marrow fibrosis. This is in addition to the presence of molecular genetic marker specific for MPN including JAK-2, MPL and CALR. Making a diagnosis of MPN in absence of the previously mentioned features is always challenging. Herein, we analyze the clinical, pathologic and molecular genetics features for five cases presented with splanchnic vein thrombosis and found to be positive for JAK-2 V617F. However, from the hematpathologic point of view, apart from JAK-2 positivity, none of these cases had fulfilled the WHO diagnostic criteria for MPNs. Although the BM specimens were reviewed by at least two experienced hematopathologists, it was so difficult to conclude the diagnosis and or do further sub classification into a specific MPN category. Objective: The aim of this report is to highpoint the difficulty in establishing the diagnosis within this group of patients based on the current WHO diagnostic criteria, to focus on BM pathologic features of this group of patients. Patients and Methods: The patients reported here were referred to our center presenting with portal vein, superior mesenteric or splenic vein thrombosis. Five adult female patients were recognized (2015 and 2019). The mean age at diagnosis is 40.8 years (27-56). None of these cases had an increase in peripheral blood counts except for patient (1) which had mild leukocytosis and thrombocytosis. All patients showed normocellular or slightly hypercellular BM. Slight erythroid predominance was reported in patient (2) and (4). Megakaryocytes were increased in all patients except for patient (2). Interestingly, megakaryocytes morphology was similar in all five patients as they showed anisocytosis with some degree of pleomorphism with predominant of large forms, no clustering and no abnormal topography was noted (figure 1 and 2). All patients showed no significant increase in reticulin fibrosis. Sub-classification into a specific MPN category cannot be performed in all patients. Next generation sequence had been used to analyze targeted regions in recurrently mutated genes in myeloid neoplasia. JAK-2V617F mutation was detected in all studied patients. In patient number (2) JAK-2 mutation was detected at a low level (4%), however, on follow-up, the mutation level increased in addition to detection of 3bp insertion/deletion in CALR gene resulting in a mutation other than type I or type II. table (1). Discussion: Splanchnic veins thrombosis (SVT) includes the portal vein thrombosis (PVT), mesenteric (MVT) splenic vein thrombosis, and the Budd Chiari syndrome (BCS). SVTs are rare events, estimated by 0.7 per 100,000 patients per year for PVT [Rajani et al. 2010]. In a laboratory setting, the diagnosis of latent MPN in patients with SVT is challenging due to absence of elevated blood counts, probably caused by portal hypertension and splenomegaly that result from SVT and MPN. However, the reason why this group of patients does not have overt features of myeloproliferation (particularly) the hypercellularity in the BM is not yet clear. It is possible that JAK-2 positivity induced venous thrombosis longer time before development of the full blown picture of MPN. However, follow-up BM studies for this group of patients might help in better characterization of the pathologic features of these patients. These patients are included in the MPN, unclassifiable subcategory in the current WHO classification. However, based on our findings and the previously published data it seems that these patients have distinctive clinical and pathological features that necessitate having them in a separate MPN entity that might have less strict diagnostic criteria that might include clinical symptoms especially venous thrombosis in large vessels. Separating this group of patients will help to study them thoroughly. Disclosures No relevant conflicts of interest to declare.

JAK2V617F Mutation Screening as Part of the Hypercoagulable Workup in the Absence of Splanchnic Vein Thrombosis: Assessment of Value in a Series of 664 Consecutive Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3191-3191
Author(s):  
Animesh Pardanani ◽  
Terra L. Lasho ◽  
Kebede Hussein ◽  
Susan Schwager ◽  
Christy Finke ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Mutation Screening ◽  
Prothrombin G20210a ◽  
Cerebral Vein ◽  
Assay Sensitivity ◽  
Splanchnic Vein Thrombosis ◽  
Vein Thrombosis ◽  
G20210a Mutation ◽  
Central Retinal Vein

Abstract Background: JAK2V617F is a recurring mutation in patients with polycythemia vera (PV) (95%) and essential thrombocythemia (ET) (50%), diseases that are frequently complicated by arterial and/or venous thrombosis. JAK2V617F is also frequently identified in patients with splanchnic vein thrombosis, including in those with occult myeloproliferative disorder (MPD). We previously reported a low prevalence of JAK2V617F in thrombosis patients - only 2% of 210 patients with non-splanchnic vein thrombosis (Leukemia, 2007 Aug;21(8):1828–9), and <1% of 136 patients with arterial stroke (J Thromb Haemost. 2007 Aug;5(8):1784–5). Here, we expanded the analysis to 664 thrombosis patients to describe: JAK2V617F prevalence, and clinical course of patients harboring this mutation. Methods: In Phase I, we screened 439 consecutive patients who underwent thrombophilia testing at our institution in early 2005 - patients with splanchnic vein thrombosis or overt MPD were excluded. In Phase II, we identified 228 additional patients considered to be at high risk for harboring JAK2V617F, who were seen at our institution from 2004 to 2006. JAK2V617F screening (assay sensitivity <1%) was performed as described in the aforementioned references. Results: In the initial cohort of 439 patients (median age=56 years; range 17–93 years; 222 female), 136 (31%) presented with stroke, 114 (26%) with deep venous thrombosis (DVT), 95 (22%) with pulmonary embolism (PE), 50 (11%) with DVT and PE, 10 (2%) with central retinal vein occlusion (CRVO), 7 (2%) with cerebral vein thrombosis, and the remaining 27 (6%) with other thromboses. Five patients (MC1-MC5; median age=78 years) were found to harbor JAK2V617F (prevalence=1%) - none had overt clinical features of MPD and all harbored a low level of JAK2V617F in peripheral blood (median=5–2%; range=2.2–7.5%) (Table). One patient (MC2) carried the Prothrombin G20210A mutation In the subsequent cohort, we studied 197 patients (median age=39 years; range=16–84 years) with recurrent DVT and/or PE, and 28 patients (median age=27 years; range=31–49 years) with acute myocardial infarction at a young age (<50 years). One patient (MC6) who presented with recurrent idiopathic DVT was found to harbor JAK2V617F (prevalence <0.5%) (Table) - this patient had no features of underlying MPD and the mutation burden was low (9%). After a median follow up of 27 months (range=4–66 months), none of the 6 patients harboring JAK2V617F has developed overt MPD. Conclusions: In patients with thrombosis, JAK2V617F is infrequently detected in the absence of overt MPD and/or involvement of splanchnic veins. Thus, JAK2V617F screening cannot be recommended as part of the hypercoagulable workup in routine clinical practice in this setting. The risk of developing overt MPD may be quite low for patients harboring a low JAK2V617F burden at the time of thrombosis although longer follow up is needed in this regard. Furthermore, the thrombosis risk may be well controlled with standard warfarin therapy, and the role of myelosuppressive agents (eg. hydroxyurea) is unclear in these patients. Characteristics of patients harboring JAK2V617F Patient Age Sex Thrombosis JAK2V617F allele burden MPD Follow up (months) Status MC1 84 M PE, DVT 5.3% No 66 Alive MC2 82 F PE, cerebral vein 5% No 38 Alive MC3 74 F PE 2.2% No 4 Dead MC4 78 F Central retinal vein 5.2% No 22 Alive MC5 63 M Stroke 7.5% No 30 Alive MC6 69 M Recurrent DVT No No 24 Alive

Pathogenesis and Management of Thrombotic Disease in Myeloproliferative Neoplasms

2019 ◽  
Vol 45 (06) ◽  
pp. 604-611 ◽  
Author(s):  
Deepa RJ Arachchillage ◽  
Mike Laffan
Keyword(s):  
Venous Thrombosis ◽  
Myeloproliferative Neoplasms ◽  
Vitamin K Antagonists ◽  
Previous History ◽  
Disease Patient ◽  
Related Factors ◽  
Hematopoietic Stem ◽  
Splanchnic Vein Thrombosis ◽  
Vein Thrombosis ◽  
Cell Counts

AbstractChronic myeloproliferative neoplasms (MPN) are characterized by clonal expansion of an abnormal hematopoietic stem/progenitor cell and include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Venous thrombosis, often at unusual sites, including splanchnic vein thrombosis and arterial thrombosis, as well as a hemorrhagic tendency and a propensity to transform into myelofibrosis or acute leukemia are common complications in patients with MPNs. The pathogenesis of thrombosis in MPN patients is complex and multifactorial. Disease related factors, such as an increase in blood cell counts (i.e., leukocytosis, erythrocytosis, and thrombocytosis), and more importantly presence of JAK2 mutation can interact with non-disease patient related factors such as age, previous history of thrombotic events, obesity, hypertension, hyperlipidemia, and presence of thrombophilic defects. The overall rate of recurrent thrombosis after venous thromboembolism (VTE) is 6.0 to 6.5 per 100 patient-years in patients with MPN compared to 2.7 to 3.7 per 100 patient-years in patients without MPN, and antithrombotic therapy with vitamin K antagonists (VKAs) is associated with a clear benefit, reducing the incidence of recurrence by 48 to 69%. Life-long oral anticoagulation with VKAs is the cornerstone of the antithrombotic treatment for splanchnic vein thrombosis (SVT). Patients with MPN-related cerebral venous thrombosis (CVT) should also be treated with long-term anticoagulation with VKAs. The role of direct acting oral anticoagulants in patients with thrombosis and MPN is not established and the use of these anticoagulants should be considered on an individual basis according to the risk of recurrent of VTE and bleeding.

JAK2 Germline Genetic Variation In Budd-Chiari Syndrome and Portal Vein Thrombosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4212-4212
Author(s):  
Jasper Smalberg ◽  
Edith Koehler ◽  
Sarwa Darwish Murad ◽  
Aurelie Plessier ◽  
Juan-Carlos Garcia-Pagan ◽  
...  
Keyword(s):  
Portal Vein ◽  
Portal Vein Thrombosis ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Budd Chiari Syndrome ◽  
Single Nucleotide ◽  
Vein Thrombosis ◽  
Chiari Syndrome

Abstract Abstract 4212 Primary Budd-Chiari syndrome (BCS) and non-malignant, non-cirrhotic portal vein thrombosis (PVT) are rare disorders with a considerable overlap in etiology. Myeloproliferative neoplasms (MPN) are the most frequent underlying prothrombotic factor in both entities. The JAK2 V617F mutation (VF) has been identified in over half of the individuals with MPN. Recently, a JAK2 haplotype, designated ‘46/1’, has been described. Previous studies suggest that the JAK2 46/1 haplotype represents a disease susceptibility to MPN, independent of VF status. The aim of this study was to determine the role of the JAK2 46/1 haplotype in the etiology of BCS and PVT. Patients were recruited from the EN-Vie cohort, consisting of 163 BCS and 138 PVT patients, consecutively enrolled in nine European countries between October 2003 and October 2005. DNA was available from 116 BCS patients (50 males and 66 females; median age 38.1), 97 PVT patients (47 males and 50 females; median age 49.8) and 104 healthy controls (43 males and 61 females; median age 36.8). The JAK2 46/1 haplotype was tagged by the rs12343867 single nucleotide polymorphism. Frequency of the JAK2 haplotype 46/1 was higher in BCS (36%, p=0.06) compared to controls (27%), while similar in PVT patients (28%, p=0.89). When stratified for VF status, haplotype 46/1 frequency was higher in VF positive BCS (44%, p=0.01) and VF positive PVT patients (40%, p=0.06) compared to controls. Haplotype 46/1 frequency was similar in VF negative BCS (33%, p=0.29) and PVT patients (24%, p=0.47) compared to controls. VF negative BCS patients with a proven MPN also showed increased frequency of the 46/1 haplotype (56%, p=0.07). Logistic regression, adjusted for age and sex, showed an association between the 46/1 haplotype and risk of VF positive BCS (OR: 2.10; 1.16–3.80), VF positive PVT (OR 2.07; 0.95–4.52) and VF negative BCS patients with a proven MPN (OR 3.04; 1.02–9.06). We conclude that the JAK2 46/1 haplotype may be associated with BCS and that this was limited to patients with a proven MPN, independent of VF status. In PVT, the 46/1 haplotype was only associated with patients who were VF positive. This study was carried out on behalf of the European Network for Vascular Disorders of the Liver (EN-Vie). Disclosures: No relevant conflicts of interest to declare.

Splanchnic Vein Thrombosis Associated With Myeloproliferative Neoplasms. A Study Of The IWG-MRT In 475 Subjects

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1582-1582 ◽  
Author(s):  
Lisa Pieri ◽  
Paola Guglielmelli ◽  
Massimo Primignani ◽  
Cecilia Brambilla ◽  
Maria Luigia Randi ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Hepatic Failure ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Biological Data ◽  
Budd Chiari Syndrome ◽  
Vein Thrombosis ◽  
Mutational Status ◽  
Chiari Syndrome

Abstract Philadelphia-negative Myeloproliferative Neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Myelofibrosis Primary (PMF) and secondary to PV and ET (PPV-, PET-MF); included are also some less characterized entities defined as unclassified MPN (U-MPN). Risk of arterial and venous thrombosis is increased in MPN patients, and thrombosis is one of most important causes of mortality and morbidity. The risk of venous thrombosis in unusual sites, such as splanchnic vessels (SVT), is particularly associated with MPN; SVT can lead to complications such as portal hypertension, esophageal and gastric varices, ascites and hepatic failure. A recent meta-analysis reported that a MPN is the underlying cause of portal vein thrombosis in 31.5% and of Budd Chiari syndrome in 40.9% of cases (Smalberg, 2012). A significant association of SVT with JAK2V617F mutated MPN was reported (Dentali, 2009) but study of other correlations has been hampered by heterogeneity of available patient cohorts comprising relatively small number of cases. We conducted a retrospective multicenter study collecting clinical and biological data of patients (pts) with SVT associated with MPN diagnosed according to WHO2008 criteria, aiming to describe patients’ characteristics, trends and prognostic factors, and their potential implications for clinical practice. Data were collected from 15 international hematology centers in the framework of IWG-MRT. We collected 475 cases of pts with portal, splenic or mesenteric vein thrombosis (75.2%) or Budd Chiari syndrome (24.8%) associated with MPN. In 32% of cases, simultaneous involvement of portal (69.1% of total thrombosis), splenic (30.5%) and mesenteric (25.3%) veins occurred, and in 1.7% they were associated with Budd Chiari syndrome. Frequency of MPN subtype: 38.1% ET (n=181), 34.9% PV (n=166), 16.2% MF (n=77), 10.8% U-MPN (n=51). Median follow-up 87.9 mo (range 0.5-430); female 61.3% (n=292; P<0.0001 vs male); median age at MPN diagnosis (dg) 44.4 y (range 12-90), at SVT dg 44.9 y (range 17-85). In 229 cases (48%) MPN and SVT dg were coincident, while in 104 (22%) SVT occurred before MPN dg (median 40 mo, range 5-335) and in 129 (27%) during MPN follow up (median 79 mo, range 5-394). JAK2V617F mutational status is available for 361 pts: 99% PV, 84.7% ET, 88.1% PMF and 92.9% U-MPN pts were JAK2V617F positive, with a mean allele burden of 56±27.4%, 33.1±25.5%, 39.3±19.4% and 23.8±11.9%, respectively. Erythropoietin-independent colonies (EEC) were present at diagnosis in 80/110 evaluated cases (72.7%), 38/47 PV (84.4%), 32/45 ET (71.1%), 8/11 PMF (72.7%) and 2/7 U-MPN (28.6%). A concurrent thrombophilic state was found in 38.9% of cases. A 12.3% of pts experienced a recurrence of SVT after a median of 29 mo (range 1-378.3) and 35.8% developed thrombosis in other sites (17.7% arterial, 19.3% venous). Esophageal varices were found in 70.6% from which 31.9% bled. MF transformation occurred in 32/166 PV (19%) and in 23/181 ET (13%) pts, with median time to progression of 122.3 mo (range 5.4-377.3) and 125.1 mo (range 39.3-255.3), respectively. Evolution to acute leukemia (AL) occurred in 12 pts (2.7%), of which 2 PMF, 6 PV and 4 ET. In 3 PV and 1 ET pts a PPV and PET-MF transformation occurred before AL. After SVT, 77% of pts received anticoagulation, 23.5% antiaggregant therapy and 1.5% both; 68.8% received cytotoxic drugs, 11.4% of pts were treated with trans jugular porto-systemic shunt. No differences in survival were noted with these approaches. Beta blocker therapy was used in 48.5% of pts and correlated with improved survival (p=0.041) At last follow up 70/473 pts (14.8%) died; causes of death are evolution to AL (16.4%), other cancers (14.5%), disease progression without AL (12.7%), SVT (10.9%), hepatic failure and venous thrombosis other than SVT (9.1% each), heart failure and arterial thrombosis (7.3% each), hemorrhage (5.5%), renal failure and infection (3.6% each). After 10 y follow up 8/166 PV (5%), 14/181 ET (8%), 14/77 PMF (18%) and 1/51 U-MPN (1.96%) pts died (p<0.01). Survival was significantly affected by occurrence of thrombosis other than SVT (p<0.0001) but not recurrence in splanchnic vessels (p=0.068). This large study confirms the strong association between JAK2V617F-mutated MPN and SVT and identifies the category of U-MPN as the prognostically more favorable; thrombosis at sites outside the splanchnic vasculature remains the leading cause of death. Disclosures: No relevant conflicts of interest to declare.

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